Triazolopyrimidine compounds and uses thereof

ABSTRACT

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder:wherein R1, R2, R3, R4, R5, and n are as defined herein.

FIELD OF THE INVENTION

The present disclosure relates to triazolopyrimidine compounds,compositions comprising such compounds, and their use for the treatmentof Polycomb Repressive Complex 2 (PRC2)-mediated diseases or disorders.

BACKGROUND

Polycomb group (PcG) proteins are chromatin modifying enzymes that aredysregulated in many human cancers. The Polycomb Repressive Complex 2(PRC2), which includes SUZ12 (suppressor of zeste 12), EED (embryonicectoderm development) and the catalytic subunit, EZH2 (enhancer of zestehomolog 2), represses genes by methylating the core histone H3 lysine 27(H3K27me3) at and around the promoter regions of target genes. PRC2 isthe critical component of cellular machinery involved in the epigeneticregulation of gene transcription and plays critical function indevelopment and tissue differentiation and regeneration. Although EZH2is the catalytic subunit, PRC2 requires at least EED and SUZ12 for itsmethyltransferase activity. EED, SUZ12 and EZH2 are overexpressed inmany cancers, including but not limited to breast cancer, prostatecancer, hepatocellular carcinoma and etc. EZH2 activating mutations havebeen identified in DLBCL (diffused large B cell lymphoma) patients andFL (follicular lymphoma) patients. Inhibition of PRC2 methyltransferaseactivity by compounds competing with the cofactor S-adenosyl methionine(SAM) in DLBCL reverses H3K27 methylation, re-activates expression oftarget genes and inhibits tumor growth/proliferation. Therefore, PRC2provides a pharmacological target for DLBCL and other cancers. Inparticular, the need exists for small molecules that inhibit theactivity of PRC2. The present invention fulfills this need.

SUMMARY

The present disclosure provides a compound of Formula (I):

wherein R¹, R², R³, R⁴, R⁵, and n are as defined herein, includingstereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs,or solvates thereof, which are useful for the treatment of PRC2-mediateddiseases or disorders.

The present disclosure also provides processes and intermediates formaking the compounds of the present disclosure.

The present disclosure also provides pharmaceutical compositionscomprising at least one of the compounds of the present disclosure andat least one pharmaceutically acceptable carrier, diluent or excipient.The pharmaceutical composition may further comprise at least oneadditional therapeutic agent. Of particular interest are additionaltherapeutic agents selected from: other anti-cancer agents,immunomodulators, anti-allergic agents, anti-nausea agents (oranti-emetics), pain relievers, cytoprotective agents, and combinationsthereof.

The compounds of the present disclosure may be used in the treatment ofdiseases or disorders mediated by EED and/or PRC2.

The compounds of the present disclosure may be used in therapy.

The compounds of the present disclosure may be used for the manufactureof a medicament for the treatment of diseases or disorders mediated byEED and/or PRC2.

The present disclosure provides a method for the treatment of diseasesor disorders mediated by EED and/or PRC2, comprising administering to apatient in need thereof a therapeutically effective amount of a firsttherapeutic agent optionally with a second therapeutic agent, whereinthe first therapeutic agent is a compound of the present disclosure andthe second therapeutic agent is one other type of therapeutic agent.

Examples of diseases or disorders mediated by EED and/or PRC2 include,but are not limited to, diffused large B cell lymphoma (DLBCL),follicular lymphoma, other lymphomas, leukemia, multiple myeloma,mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellularcarcinoma, prostate cancer, breast carcinoma, bile duct and gallbladdercancers, bladder carcinoma, brain tumors including neuroblastoma,schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, coloncancer, melanoma, endometrial cancer, esophageal cancer, head and neckcancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer,pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancers,parathyroid tumors, uterine tumors, and soft tissue sarcomas such asrhabdomyosarcoma (RMS), Kaposi sarcoma, synovial sarcoma, osteosarcomaand Ewing's sarcoma.

The present disclosure provides a method for the treatment of diseasesor disorders mediated by EED and/or PRC2, comprising administering to apatient in need thereof a therapeutically effective amount of a firsttherapeutic agent optionally with a second therapeutic agent, whereinthe first therapeutic agent is an EED inhibitor and the secondtherapeutic agent is one other type of therapeutic agent; wherein thediseases or disorders are selected from diffused large B cell lymphoma(DLBCL), follicular lymphoma, other lymphomas, leukemia, multiplemyeloma, gastric cancer, malignant rhabdoid tumor, and hepatocellularcarcinoma.

The compounds of the present disclosure can be used alone, incombination with other compounds of the present disclosure, or incombination with one or more, preferably one to two other agent(s),simultaneously or sequentially.

Other features and advantages of the present disclosure will be apparentfrom the following detailed description and claims.

DETAILED DESCRIPTION I. Compounds

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

is a single bond or a double bond;

R¹ and R² are independently H or halogen;

R³ is independently selected from: halogen, phenyl, and a 5- to6-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(a), O, and S(O)_(p); wherein said phenyl andheteroaryl are substituted with 0-3 R^(3A);

each R^(3A) is independently selected from: halogen, CN, —(O)_(m)—(C₁-C₆alkyl substituted with 0-1 R^(3B)), C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,R^(3C), —OR^(3C), —C(═O)R^(3D), NR^(3E)R^(3F), —C(═O)NR^(3E)R^(3F),—NHC(═O)R^(3D), —S(═O)₂R^(3D), —S(═O)₂NR^(3E)R^(3F), —NHS(═O)₂(C₁-C₄alkyl), and —CR^(3C)R^(3E)R^(3G);

R^(3B) is independently selected from: OH, NR^(e)R^(f), C₁-C₄ alkoxy,—C(═O)NR^(e)R^(f), —S(═O)₂(C₁-C₄ alkyl), —NHC(═O)(C₁-C₄ alkyl), and a 5-to 6-membered heterocycloalkyl comprising carbon atoms and 1-2heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein saidheterocycloalkyl is substituted with 0-2 R^(c);

each R^(3C) is independently selected from: C₃-C₆ cycloalkyl, phenyl,and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein eachmoiety is substituted with 0-2 R^(c);

each R^(3D) is independently selected from: C₁-C₄ alkyl and R^(3C);R^(3E) and R^(3G) are, at each occurrence, independently selected from:H and C₁-C₄ alkyl;

each R^(3F) is independently selected from: H and C₁-C₄ alkylsubstituted with 0-1 R^(d);

R⁴ is independently selected from: H, halogen and C₁-C₄ alkyl;

R⁵ is independently selected from OH and C₁-C₄ alkyl;

each R^(a) is independently selected from: H, →O, C₁-C₄ alkylsubstituted with 0-1 R^(b), —C(═O)H, —C(═O)(C₁-C₄ alkyl), —CO₂(C₁-C₄alkyl), C₃-C₆ cycloalkyl, and benzyl;

R^(b) is independently selected from: halogen, OH and C₁-C₄ alkoxy;

each R^(c) is independently selected from: ═O, halogen, OH, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy;

R^(d) is independently selected from: OH and NR^(e)R^(f);

R^(e) and R^(f) are, at each occurrence, independently selected from: Hand C₁-C₄ alkyl;

each p is independently selected from 0, 1 and 2; and

m and n are, at each occurrence, independently selected from 0 and 1.

In another aspect, the present disclosure provides a compound of Formula(IA):

or a pharmaceutically acceptable salt thereof, within the scope of thefirst aspect; wherein:

R¹ and R² are independently H or halogen;

R³ is independently selected from: halogen, phenyl, and a 5- to6-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(a), O, and S(O)_(p); wherein said phenyl andheteroaryl are substituted with 0-3 R^(3A);

each R^(3A) is independently selected from: halogen, CN, —(O)_(m)—(C₁-C₆alkyl substituted with 0-1 R^(3B)), OC—O₆ haloalkyl, C₁-C₆ haloalkoxy,R^(3C), —OR^(3C), —C(═O)R^(3D), NR^(3E)R^(3F), —C(═O)NR^(3E)R^(3F),—NHC(═O)R^(3D), —S(═O)₂R^(3D), —S(═O)₂NR^(3E)R^(3F), —NHS(═O)₂(C₁-C₄alkyl), and —CR^(3C)R^(3E)R^(3G);

R^(3B) is independently selected from: OH, NR^(e)R^(f), C₁-C₄ alkoxy,—C(═O)NR^(e)R^(f), —S(═O)₂(C₁-C₄ alkyl), —NHC(═O)(C₁-C₄ alkyl), and a 5-to 6-membered heterocycloalkyl comprising carbon atoms and 1-2heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein saidheterocycloalkyl is substituted with 0-2 R^(c);

each R^(3C) is independently selected from: C₃-C₆ cycloalkyl, phenyl,and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein eachmoiety is substituted with 0-2 R^(c);

each R^(3D) is independently selected from: C₁-C₄ alkyl and R^(3C);

R^(3E) and R^(3G) are, at each occurrence, independently selected from:H and C₁-C₄ alkyl;

each R^(3F) is independently selected from: H and C₁-C₄ alkylsubstituted with 0-1 R^(d);

R⁴ is independently selected from: H, halogen and C₁-C₄ alkyl;

R⁵ is independently C₁-C₄ alkyl;

each R^(a) is independently selected from: H, →O, C₁-C₄ alkylsubstituted with 0-1 R^(b), —C(═O)H, —C(═O)(C₁-C₄ alkyl), —CO₂(C₁-C₄alkyl), C₃-C₆ cycloalkyl, and benzyl;

R^(b) is independently selected from: halogen, OH and C₁-C₄ alkoxy;

each R^(c) is independently selected from: =0, halogen, OH, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy;

R^(d) is independently selected from: OH and NR^(e)R^(f);

R^(e) and R^(f) are, at each occurrence, independently selected from: Hand C₁-C₄ alkyl;

each p is independently selected from 0, 1 and 2; and

m and n are, at each occurrence, independently selected from 0 and 1.

In a second aspect, the present disclosure includes a compound ofFormula (I) or (IA), or a pharmaceutically acceptable salt thereof,within the scope of the first aspect; wherein:

each R^(3A) is independently selected from: halogen, CN, —(O)_(m)—(C₁-C₄alkyl substituted with 0-1 R^(3B)), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,R^(3C), —C(═O)R^(3D), NR^(3E)R^(3F), —C(═O)NR^(3E)R^(3F), —S(═O)₂R^(3D),—S(═O)₂NHR^(3F), —NHS(═O)₂(C₁-C₄ alkyl), —O—C₃-C₆ cycloalkyl, and

R^(a) is independently selected from: H, →O, C₁-C₄ alkyl substitutedwith 0-1 R^(b), —C(═O)H, —C(═O)(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), andC₃-C₆ cycloalkyl;

R⁴ is H;

m is independently selected from 0 and 1; and

n is 0.

In a third aspect, the present disclosure includes a compound of Formula(I) or (IA), or a pharmaceutically acceptable salt thereof, within thescope of the first or second aspect; wherein:

R¹ is independently H or F;

R² is H; and

R³ is independently selected from: phenyl and a 6-membered heteroarylcomprising carbon atoms and 1-2 heteroatoms selected from N and NR^(a);wherein said phenyl and heteroaryl are substituted with 0-3 R^(3A).

In a fourth aspect, the present disclosure includes a compound ofFormula (I) or (IA), or a pharmaceutically acceptable salt thereof,within the scope of any one of the first, second and third aspects;wherein:

R³ is independently selected from: phenyl, pyridyl, pyrimidyl,pyridazinyl and pyrazinyl; wherein each moiety is substituted with 0-3R^(3A).

In a fifth aspect, the present disclosure includes a compound of Formula(I) or (IA), or a pharmaceutically acceptable salt thereof, within thescope of any of the first to fourth aspects, wherein:

R³ is independently selected from:

In a sixth aspect, the present disclosure includes a compound of Formula(I) or (IA), or a pharmaceutically acceptable salt thereof, within thescope of any of the first to fifth aspects, wherein:

R³ is independently selected from:

each R^(3A) is independently selected from: halogen, CN, —(O)_(m)—(C₁-C₄alkyl substituted with 0-1 R^(3B)), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,—C(═O)NH₂, —C(═O)NH(C₁-C₄ alkyl), —C(═O)N(C₁-C₄ alkyl)₂, —C(═O)N(C₁-C₄alkyl)(CH₂)₂N(C₁-C₄ alkyl)₂, —CH₂NHC(═O)(C₁-C₄ alkyl), —S(═O)₂R^(3D),—S(═O)₂NH(C₁-C₄ alkyl substituted with 0-1 OH), —NHS(═O)₂(C₁-C₄ alkyl),NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, C₃-C₆ cycloalkyl,

R^(3B) is independently selected from: OH, NH₂, NH(C₁-C₄alkyl),N(C₁-C₄alkyl)₂, C₁-C₄ alkoxy, —C(═O)N(C₁-C₄ alkyl)₂, —S(═O)₂(C₁-C₄alkyl),

R^(3D) is independently selected from: C₁-C₄ alkyl and1H-piperidin-4-yl; and

each R^(a) is independently selected from: H, C₁-C₄ alkyl, —C(═O)H,—C(═O)(C₁-C₄ alkyl), and —CO₂(C₁-C₄ alkyl).

In a seventh aspect, the present disclosure includes a compound ofFormula (I) or (IA), or a pharmaceutically acceptable salt thereof,within the scope of any of the first to sixth aspects, wherein:

R³ is independently selected from:

each R^(3A) is independently selected from: halogen, ON, —(O)_(m)—(C₁-C₄alkyl substituted with 0-1 R^(3B)), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,—C(═O)NH₂, —C(═O)NH(C₁-C₄ alkyl), —C(═O)N(C₁-C₄ alkyl)₂, —C(═O)N(C₁-C₄alkyl)(CH₂)₂N(C₁-C₄ alkyl)₂, —CH₂NHC(═O)(C₁-C₄ alkyl), —S(═O)₂(C₁-C₄alkyl), NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl)₂, C₃-C₆ cycloalkyl,

R^(3B) is independently selected from: OH, N(C₁-C₄ alkyl)₂, C₁-C₄alkoxy,—C(═O)N(C₁-C₄ alkyl)₂, —S(═O)₂(C₁-C₄ alkyl),

each R^(a) is independently selected from: H, C₁-C₄ alkyl, —C(═O)H,—C(═O)(C₁-C₄alkyl), and —CO₂(C₁-C₄alkyl).

In an eighth aspect, the present disclosure includes a compound ofFormula (I) or (IA), or a pharmaceutically acceptable salt thereof,within the scope of any of the first to seventh aspects, wherein:

each R^(3A) is independently selected from: F, Cl, CH₃, —CH₂OH, CH₂F,CHF₂, CF₃, CN, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCHF₂, —C(═O)N(CH₃)₂,—CH₂NHC(═O)CH₃, —S(═O)₂CH₃, NH₂, cyclopropyl,

In a ninth aspect, the present disclosure provides a compound of Formula(IA-1):

or a pharmaceutically acceptable salt thereof, within the scope of anyof the above aspects; wherein:

R¹ is independently H or F; and

R^(3A) is independently selected from: F, CH₃, —CH₂OH, CH₂F, CHF₂, CF₃,and —OCH₃.

In a tenth aspect, the present disclosure includes a compound of Formula(I) or (IA), or a pharmaceutically acceptable salt thereof, within thescope of the first or second aspect; wherein:

R¹ is independently H or F;

R² is H;

R³ is independently a 5-membered heteroaryl comprising carbon atoms and1-4 heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein saidheteroaryl is substituted with 0-3 R^(3A); and

R^(a) is independently selected from: H, C₁-C₄ alkyl substituted with0-1 R^(b), —C(═O)H, —C(═O)(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), C₃-C₆cycloalkyl, and benzyl.

In an eleventh aspect, the present disclosure includes a compound ofFormula (I) or (IA), or a pharmaceutically acceptable salt thereof,within the scope of any one of the first, second and tenth aspects;wherein:

R³ is independently selected from:

In another aspect, the present disclosure includes a compound of Formula(I) or (IA), or a pharmaceutically acceptable salt thereof, within thescope of any one of the first, second and tenth aspects; wherein:

R³ is independently selected from:

In a twelfth aspect, the present disclosure includes a compound ofFormula (I) (IA), or (IA-1), or a pharmaceutically acceptable saltthereof, within the scope of any of the above aspects, wherein:

R¹ is F.

In a thirteenth aspect, the present disclosure provides a compoundselected from the exemplified examples or a pharmaceutically acceptablesalt thereof, including all compounds of Examples 1 to 245.

In a fourteenth aspect, the present disclosure provides a compoundselected from:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided is a compound of Example 1 or apharmaceutically acceptable salt thereof, wherein the compound is8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 1, wherein thecompound is8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 2 or apharmaceutically acceptable salt thereof, wherein the compound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 2, wherein thecompound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 5 or apharmaceutically acceptable salt thereof, wherein the compound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-4-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 5, wherein thecompound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-4-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 8 or apharmaceutically acceptable salt thereof, wherein the compound is8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 8, wherein thecompound is8-(2-cyclopropyl-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 207 or apharmaceutically acceptable salt thereof, wherein the compound isN-((5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 207, whereinthe compound isN-((5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 233 or apharmaceutically acceptable salt thereof, wherein the compound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another embodiment, provided is a compound of Example 233, whereinthe compound isN-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine.

In another aspect, the present disclosure provides a compound or apharmaceutically acceptable salt thereof, selected from any subset listof compounds within the scope of the thirteenth aspect.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first toseventh aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, —CON(C₁-C₄ alkyl)₂, —S(═O)₂(C₁-C₄ alkyl), and C₃-C₆cycloalkyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first toseventh aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: CH₃, OCH₃, —CON(CH₃)₂,—S(═O)₂(CH₃), and cyclopropyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first toseventh aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: C₁-C₄ alkoxy, C₁-C₄haloalkoxy, and —O—C₃-C₆ cycloalkyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first toseventh aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: OCH₃, OCH₂CH₃, —OCHF₂, and—O-cyclopropyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first toseventh aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: C₁-C₄ alkoxy, C₁-C₄haloalkoxy, and —O—C₃-C₆ cycloalkyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first tosixth aspects, wherein:

R³ is independently

and

each R^(3A) is independently selected from: halogen, CN, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, N(C₁-C₄ alkyl)₂, andC₃—C cycloalkyl.

In another embodiment, provided is the compound or a pharmaceuticallyacceptable salt thereof, within the scope of any one of the first tosixth aspects, wherein:

R³ is independently

each R^(3A) is independently selected from: halogen, CN, —(O)_(m)—(C₁-C₄alkyl substituted with 0-1 R^(3B)), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,C(═O)NH₂, —S(═O)₂R^(3C), —S(═O)₂NH(C₁-C₄ alkyl substituted with 0-1 OH),—NHS(═O)₂(C₁-C₄ alkyl),

R^(3B) is independently selected from: OH, NH₂, N(C₁-C₄ alkyl)₂, and—S(═O)₂(C₁-C₄ alkyl); and

R^(3c) is independently selected from: C₁-C₄ alkyl and1H-piperidin-4-yl.

In another aspect, the present disclosure includes a compound of Formula(IA), or a pharmaceutically acceptable salt thereof, within the scope ofany one of the first, second, tenth, and eleventh aspects; wherein:

R³ is independently selected from: and

In another aspect, the present disclosure includes a compound of Formula(IA), or a pharmaceutically acceptable salt thereof, within the scope ofany one of the first, second, tenth, and eleventh aspects; wherein:

R³ is independently

each R^(3A) is independently selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;

R^(a) is independently selected from: H, C₁-C₄ alkyl substituted with0-1 R^(b), and C₃-C₆ cycloalkyl; and

R^(b) is independently selected from: OH and C₁-C₄ alkoxy.

In another embodiment, the compounds of the present disclosure have IC50values ≤5 μM, using the EED Alphascreen binding, LC-MS and/or ELISAassays disclosed herein, preferably, IC₅₀ values ≤1 μM, more preferably,IC₅₀ values ≤0.5 μM, even more preferably, IC₅₀ values ≤0.1 μM.

II. Other Embodiments

In another embodiment, the present disclosure provides a compositioncomprising at least one of the compounds of the present disclosure or apharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising at least one of the compounds of the presentdisclosure or a pharmaceutically acceptable salt thereof and at leastone pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of at leastone of the compounds of the present disclosure or a pharmaceuticallyacceptable salt thereof and at least one pharmaceutically acceptablecarrier, diluent or excipient.

The pharmaceutical composition is useful in the treatment of diseases ordisorders mediated by EED and/or PRC2.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition as defined above further comprising additional therapeuticagent(s).

In another embodiment, the present disclosure provides a process formaking a compound of the present disclosure.

In another embodiment, the present disclosure provides an intermediatefor making a compound of the present disclosure.

In another embodiment, the present disclosure provides a compound of thepresent disclosure, for use in therapy, alone, or optionally incombination with another compound of the present disclosure and/or atleast one other type of therapeutic agent.

In another embodiment, the present disclosure provides a compound of thepresent disclosure for use in therapy, for the treatment of diseases ordisorders mediated by EED and/or PRC2, alone, or optionally incombination with another compound of the present disclosure and/or atleast one other type of therapeutic agent.

In another embodiment, the present disclosure provides a method for thetreatment of diseases or disorders mediated by EED and/or PRC2,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent disclosure, alone, or optionally in combination with anothercompound of the present disclosure and/or at least one other type oftherapeutic agent.

In another embodiment, the present disclosure provides a method for thetreatment of diseases or disorders mediated by EED and/or PRC2,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a first and second therapeutic agent, wherein thefirst therapeutic agent is a compound of the present disclosure and thesecond therapeutic agent is one other type of therapeutic agent.

In another embodiment, the present disclosure also provides the use of acompound of the present disclosure for the manufacture of a medicamentfor the treatment of diseases or disorders mediated by EED and/or PRC2,alone, or optionally in combination with another compound of the presentdisclosure and/or at least one other type of therapeutic agent.

In another embodiment, the present disclosure provides a combinedpreparation of a compound of the present disclosure and additionaltherapeutic agent(s) for use in therapy.

In another embodiment, the present disclosure provides a combination ofa compound of the present disclosure and additional therapeutic agent(s)for simultaneous or separate use in therapy.

In another embodiment, the present disclosure provides a combinedpreparation of a compound of the present disclosure and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment of diseases or disorders mediated by EED and/or PRC2. Thecompound may be administered as a pharmaceutical composition describedherein.

Examples of diseases or disorders mediated by EED and/or PRC2 include,but are not limited to, diffused large B cell lymphoma (DLBCL),follicular lymphoma, other lymphomas, leukemia, multiple myeloma,mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellularcarcinoma, prostate cancer, breast carcinoma, bile duct and gallbladdercancers, bladder carcinoma, brain tumors including neurobalstoma,glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer,melanoma, endometrial cancer, esophageal cancer, head and neck cancer,lung cancer, nasopharhyngeal carcinoma, ovarian cancer, pancreaticcancer, renal cell carcinoma, rectal cancer, thyroid cancers,parathyroid tumors, uterine tumors, and soft tissue sarcomas selectedfrom rhabdomyosarcoma (RMS), Kaposi sarcoma, synovial sarcoma,osteosarcoma and Ewing's sarcoma.

In another embodiment, the present disclosure provides a method for thetreatment of diseases or disorders mediated by EED and/or PRC2,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a first optionally with a second therapeutic agent,wherein the first therapeutic agent is an EED inhibitor and the secondtherapeutic agent is one other type of therapeutic agent; wherein thediseases or disorders are selected from diffused large B cell lymphoma(DLBCL), follicular lymphoma, other lymphomas, leukemia, multiplemyeloma, gastric cancer, malignant rhabdoid tumor, and hepatocellularcarcinoma.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents: other anti-cancer agents, immunomodulators,anti-allergic agents, anti-nausea agents (or anti-emetics), painrelievers, cytoprotective agents, and combinations thereof.

Various (enumerated) embodiments of the disclosure are described herein.It will be recognized that features specified in each embodiment may becombined with other specified features to provide further embodiments ofthe present disclosure. It is also understood that each individualelement of the embodiments is its own independent embodiment.

Other features of the present disclosure should become apparent in thecourse of the above descriptions of exemplary embodiments that are givenfor illustration of the disclosure and are not intended to be limitingthereof.

III. Definitions

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated, where more general terms wherever used may,independently of each other, be replaced by more specific definitions orremain, thus defining more detailed embodiments of the invention.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

The term “a,” “an,” “the” and similar terms used in the context of thepresent disclosure (especially in the context of the claims) are to beconstrued to cover both the singular and plural unless otherwiseindicated herein or clearly contradicted by the context.

As used herein, the term “heteroatoms” refers to nitrogen (N), oxygen(O) or sulfur (S) atoms, in particular nitrogen or oxygen.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

As used herein, the terms “alkyl” refers to a hydrocarbon radical of thegeneral formula C_(n)H_(2n+1). The alkane radical may be straight orbranched. For example, the term “C₁-C₁₀ alkyl” or “C₁ to C₁₀ alkyl”refers to a monovalent, straight, or branched aliphatic group containing1 to 10 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl,heptyl, and the like).

The term “alkylene” refers to a divalent alkyl group. For example, theterm “C₁-C₆ alkylene” or “C₁ to C₆ alkylene” refers to a divalent,straight, or branched aliphatic group containing 1 to 6 carbon atoms(e.g., methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH(CH₃)CH₂—), n-butylene, sec-butylene,iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene,n-hexylene and the like).

The term “alkoxy” refers to an alkyl linked to an oxygen, which may alsobe represented as —O—R or —OR, wherein the R represents the alkyl group.“C₁-C₆ alkoxy” or “C₁ to C₆ alkoxy” is intended to include C₁, C₂, C₃,C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),and t-butoxy. Similarly, “alkylthio” or “thioalkoxy” represents an alkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example methyl-S— and ethyl-S—.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine(preferred halogens as substituents are fluorine and chlorine).

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with one or more halogens. Examples ofhaloalkyl include, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with one ormore fluorine atoms.

“Haloalkoxy” represents a haloalkyl group as defined above with theindicated number of carbon atoms attached through an oxygen bridge. Forexample, “C₁-C₆ haloalkoxy” or “C₁ to C₆ haloalkoxy” is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples ofhaloalkoxy include, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “oxo” or —C(O)— refers to a carbonyl group. For example, aketone, aldehyde, or part of an acid, ester, amide, lactone, or lactamgroup.

The term “cycloalkyl” refers to nonaromatic carbocyclic ring that isfully hydrogenated ring, including mono-, bi- or poly-cyclic ringsystems. “C₃-C₈ cycloalkyl” or “C₃ to C₈ cycloalkyl” is intended toinclude C₃, C₄, C₅, C₆, C₇ and C₈ cycloalkyl groups. Example cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and norbornyl.

The term “aryl” refers to 6- to 10-membered aromatic carbocyclicmoieties having a single (e.g., phenyl) or a fused ring system (e.g.,naphthalene.). A typical aryl group is phenyl group.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— and —S(O)₂—,wherein R is hydrogen, C₄alkyl or a nitrogen protecting group (forexample, carbobenzyloxy, p-methoxybenzyl carbonyl, t-butoxycarbonyl,acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl,3,4-dimethoxybenzyl, and the like). For example, a 3 to 8 memberedheterocycloalkyl includes epoxy, aziridinyl, azetidinyl, imidazolidinyl,pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl1,1-dioxide, oxazolidinyl, thiazolidinyl, pyrrolidinyl,pyrrolidinyl-2-one, morpholino, piperazinyl, piperidinyl,piperidinylone, pyrazolidinyl, hexahydropyrimidinyl,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino,sulfonomorpholino, octahydropyrrolo[3,2-b]pyrrolyl, and the like.

The term “partially saturated heterocycle” refers to a nonaromatic ringthat is partially hydrogenated and may exist as a single ring, bicyclicring (including fused rings). Unless specified otherwise, saidheterocyclic ring is generally a 5- to 10-membered ring containing 1 to3 heteroatoms selected from —O—, —N═, —NR—, and —S—, (preferably 1 or 2heteroatoms). Partially saturated heterocyclic rings include groups suchas dihydrofuranyl, dihydrooxazolyl, dihydropyridinyl, imidazolinyl,1H-dihydroimidazolyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl andthe like. A partially saturated heterocyclic ring also includes groupswherein the heterocyclic ring is fused to an aryl or heteroaryl ring(e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl),2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl, and the like).

The term “partially or fully saturated heterocycle” refers to anonaromatic ring that is either partially or fully hydrogenated and mayexist as a single ring, bicyclic ring (including fused rings) or aspiral ring. Unless specified otherwise, the heterocyclic ring isgenerally a 3- to 12-membered ring containing 1 to 3 heteroatoms(preferably 1 or 2 heteroatoms) independently selected from sulfur,oxygen and/or nitrogen. When the term “partially or fully saturatedheterocycle” is used, it is intended to include “heterocycloalkyl”, and“partially saturated heterocycle”. Examples of spiral rings include2,6-diazaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecanyl,3,9-diazaspiro[5.5]undecanyl, and the like.

The term “heteroaryl” refers to aromatic moieties containing at leastone heteroatom (e.g., oxygen, sulfur, nitrogen or combinations thereof)within a 5- to 10-membered aromatic ring system (e.g., pyrrolyl,pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl,oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, triazinyl,pyrimidinyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl,isoquinolinyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzoimidazolyl, benzoxazolyl, 1H-benzo[d][1,2,3]triazolyl, and thelike.). The heteroaromatic moiety may consist of a single or fused ringsystem. Atypical single heteroaryl ring is a 5- to 6-membered ringcontaining one to four heteroatoms independently selected from oxygen,sulfur and nitrogen and a typical fused heteroaryl ring system is a 9-to 10-membered ring system containing one to four heteroatomsindependently selected from oxygen, sulfur and nitrogen. The fusedheteroaryl ring system may consist of two heteroaryl rings fusedtogether or a heteroaryl fused to an aryl (e.g., phenyl).

When the term “heterocycle” is used, it is intended to include“heterocycloalkyl”, “partially or fully saturated heterocycle”,“partially saturated heterocycle”, “fully saturated heterocycle” and“heteroaryl”.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (RnNHm+, where n=0-4, m=0-4 and m+n=4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., =0), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present disclosure, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this disclosure. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group maybe unsubstituted or substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Forexample, with reference to the first aspect, this applies to 0-3 R^(3A)in the R³ definition, such that when R³ is phenyl or 5- to 6-memberedheteroaryl, these groups are either unsubstituted (not substituted withR^(3A)) or substituted with one, two or three R^(3A) groups which areindependently selected at each occurrence from the given definitions forR^(3A). This similarly applies to the definitions for 0-2 R^(c) in theR^(3B) and R^(3c) definitions, and to 0-1 R^(d) in the R^(3F)definition.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

As a person of ordinary skill in the art would be able to understand,for example, a ketone (—CH—C═O) group in a molecule may tautomerize toits enol form (—C═C—OH). Thus, this disclosure is intended to cover allpossible tautomers even when a structure depicts only one of them.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

Unless specified otherwise, the term “compounds of the presentinvention” or “compounds of the present disclosure” refers to compoundsof Formula (I), (IA) or (IA-1), as well as isomers, such asstereoisomers (including diastereoisomers, enantiomers and racemates),geometrical isomers, conformational isomers (including rotamers andastropisomers), tautomers, isotopically labeled compounds (includingdeuterium substitutions), and inherently formed moieties (e.g.,polymorphs, solvates and/or hydrates). When a moiety is present that iscapable of forming a salt, then salts are included as well, inparticular pharmaceutically acceptable salts.

It will be recognized by those skilled in the art that the compounds ofthe present disclosure may contain chiral centers and as such may existin different isomeric forms. As used herein, the term “isomers” refersto different compounds that have the same molecular formula but differin arrangement and configuration of the atoms.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. When designating the stereochemistry for the compounds ofthe present invention, a single stereoisomer with known relative andabsolute configuration of the two chiral centers is designated using theconventional RS system (e.g., (1S,2S)); a single stereoisomer with knownrelative configuration but unknown absolute configuration is designatedwith stars (e.g., (1R*,2R*)); and a racemate with two letters (e.g,(1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as aracemic mixture of (1R,2S) and (1S,2R)). “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Alternatively, theresolved compounds can be defined by the respective retention times forthe corresponding enantiomers/diastereomers via chiral HPLC.

Certain of the compounds described herein contain one or more asymmetriccenters or axes and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)—.

Geometric isomers may occur when a compound contains a double bond orsome other feature that gives the molecule a certain amount ofstructural rigidity. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

Conformational isomers (or conformers) are isomers that can differ byrotations about one or more a bonds. Rotamers are conformers that differby rotation about only a single a bond.

The term “atropisomer” refers to a structural isomer based on axial orplanar chirality resulting from restricted rotation in the molecule.

Unless specified otherwise, the compounds of the present disclosure aremeant to include all such possible isomers, including racemic mixtures,optically pure forms and intermediate mixtures. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques (e.g., separated onchiral SFC or HPLC chromatography columns, such as CHIRALPAK® andCHIRALCEL® available from DAICEL Corp. using the appropriate solvent ormixture of solvents to achieve good separation).

The present compounds can be isolated in optically active or racemicforms. Optically active forms may be prepared by resolution of racemicforms or by synthesis from optically active starting materials. Allprocesses used to prepare compounds of the present disclosure andintermediates made therein are considered to be part of the presentdisclosure. When enantiomeric or diastereomeric products are prepared,they may be separated by conventional methods, for example, bychromatography or fractional crystallization.

Depending on the process conditions the end products of the presentdisclosure are obtained either in free (neutral) or salt form. Both thefree form and the salts of these end products are within the scope ofthe disclosure. If so desired, one form of a compound may be convertedinto another form. A free base or acid may be converted into a salt; asalt may be converted into the free compound or another salt; a mixtureof isomeric compounds of the present disclosure may be separated intothe individual isomers.

Pharmaceutically acceptable salts are preferred. However, other saltsmay be useful, e.g., in isolation or purification steps which may beemployed during preparation, and thus, are contemplated within the scopeof the disclosure.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. For example, pharmaceuticallyacceptable salts include, but are not limited to, acetate, ascorbate,adipate, aspartate, benzoate, besylate, bromide/hydrobromide,bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate,chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate,fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate,glycolate, hippurate, hydroiodide/iodide, isethionate, lactate,lactobionate, laurylsulfate, malate, maleate, malonate/hydroxymalonate,mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate,nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phenylacetate, phosphate/hydrogen phosphate/dihydrogen phosphate,polygalacturonate, propionate, salicylates, stearate, succinate,sulfamate, sulfosalicylate, tartrate, tosylate, trifluoroacetate orxinafoate salt form.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, preferablyhydrochloric acid. Organic acids from which salts can be derivedinclude, for example, acetic acid, propionic acid, glycolic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and thelike.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike. Certain organic amines include isopropylamine, benzathine,cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazineand tromethamine.

The pharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

Compounds of the invention that contain groups capable of acting asdonors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of the present invention by known co-crystalforming procedures. Such procedures include grinding, heating,co-subliming, co-melting, or contacting in solution compounds of thepresent invention with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of the presentinvention.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the present disclosure include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, andchlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl,¹²⁵I respectively. The present disclosure includes various isotopicallylabeled compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹³C, and ¹⁴C, are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis present disclosure can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the present disclosure. The concentrationof such a heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of the present disclosure can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. Such compounds have a variety of potentialuses, e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this disclosure bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent disclosure do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisdisclosure with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

As used herein, “polymorph(s)” refer to crystalline form(s) having thesame chemical structure/composition but different spatial arrangementsof the molecules and/or ions forming the crystals. Compounds of thepresent disclosure can be provided as amorphous solids or crystallinesolids. Lyophilization can be employed to provide the compounds of thepresent disclosure as a solid.

“EED” refers to the protein product of the gene embryonic ectodermdevelopment.

“PRC2” refers to Polycomb Repressive Complex 2.

The term “PRC2-mediated disease or disorder” refers to any disease ordisorder which is directly or indirectly regulated by PRC2. Thisincludes, but is not limited to, any disease or disorder which isdirectly or indirectly regulated by EED.

The term “diseases or disorders mediated by EED and/or PRC2” refers todiseases or disorders which are directly or indirectly regulated by EEDand/or PRC2.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A “subject” also refers to any human or non-humanorganism that could potentially benefit from treatment with an EEDinhibitor. A subject also refers to for example, primates (e.g.,humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice,fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human. Exemplarysubjects include human beings of any age with risk factors for cancerdisease.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment (preferably, a human).

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease/disorder refers to the treatment of the disease/disorder in amammal, particularly in a human, and includes: (a) ameliorating thedisease/disorder, (i.e., slowing or arresting or reducing thedevelopment of the disease/disorder, or at least one of the clinicalsymptoms thereof); (b) relieving or modulating the disease/disorder,(i.e., causing regression of the disease/disorder, either physically,(e.g., stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both); (c) alleviating orameliorating at least one physical parameter including those which maynot be discernible by the subject; and/or (d) preventing or delaying theonset or development or progression of the disease or disorder fromoccurring in a mammal, in particular, when such mammal is predisposed tothe disease or disorder but has not yet been diagnosed as having it.

As used herein, “preventing” or “prevention” cover the preventivetreatment (i.e., prophylaxis and/or risk reduction) of a subclinicaldisease-state in a mammal, particularly in a human, aimed at reducingthe probability of the occurrence of a clinical disease-state. Patientsare selected for preventative therapy based on factors that are known toincrease risk of suffering a clinical disease state compared to thegeneral population. “Prophylaxis” therapies can be divided into (a)primary prevention and (b) secondary prevention. Primary prevention isdefined as treatment in a subject that has not yet presented with aclinical disease state, whereas secondary prevention is defined aspreventing a second occurrence of the same or similar clinical diseasestate.

As used herein, “risk reduction” or “reducing risk” covers therapiesthat lower the incidence of development of a clinical disease state. Assuch, primary and secondary prevention therapies are examples of riskreduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present disclosure that will elicit the biological ormedical response of a subject, for example, reduction or inhibition ofEED and/or PRC2, or ameliorate symptoms, alleviate conditions, slow ordelay disease progression, or prevent a disease or disorder mediated byPRC2. When applied to a combination, the term refers to combined amountsof the active ingredients that result in the preventive or therapeuticeffect, whether administered in combination, serially, orsimultaneously.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “aq” foraqueous, “Col” for column, “eq” for equivalent or equivalents, “g” forgram or grams, “mg” for milligram or milligrams, “L” for liter orliters, “mL” for milliliter or milliliters, “μL” for microliter ormicroliters, “N” for normal, “M” for molar, “nM” for nanomolar, “mol”for mole or moles, “mmol” for millimole or millimoles, “min” for minuteor minutes, “h” for hour or hours, “rt” for room temperature, “RT forretention time, “ON” for overnight, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “aq” for aqueous, “sat”or “sat'd” for saturated, MW” for molecular weight, “mw” or “pwave” formicrowave, “mp” for melting point, “Wt” for weight, “MS” or “Mass Spec”for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LC-MS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or tlc for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “1H” for proton, “6” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, “ee” for “enantiomeric excess” and “α”,“β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar toone skilled in the art.

The following abbreviations used herein below have the correspondingmeanings:

-   -   Bn benzyl    -   Boc tert-butoxy carbonyl    -   Boc₂O di-tert-butyl dicarbonate    -   Bu butyl    -   Cs₂CO₃ cesium carbonate anhydrous    -   CHCl₃ chloroform    -   DAST diethylaminosulfurtrifluoride    -   DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine    -   DCM dichloromethane    -   DMAP 4-dimethylaminopyridine    -   DMF dimethylformamide    -   DMSO dimethylsulfoxide    -   DPPA diphenylphosphoryl azide    -   EA ethyl acetate    -   Et ethyl    -   EtOH ethanol    -   EtOAc ethyl acetate    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HCl hydrochloric acid    -   i-Bu isobutyl    -   i-Pr isopropyl    -   KOAc potassium acetate    -   LiAlH₄ lithium aluminium hydride    -   LiCl lithium chloride    -   LiHMDS lithium bis(trimethylsilyl)amide    -   mCPBA 3-Chloroperoxybenzoic acid    -   Me methyl    -   Me₄-t-BuXPhos        di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphane    -   MeCN acetonitrile    -   MnO₂ manganese dioxide    -   N₂ nitrogen    -   NaBH₄ sodium borohydride    -   NaHCO₃ sodium bicarbonate    -   Na₂SO₄ sodium sulphate    -   Ph phenyl    -   PPh₃ triphenylphosphine    -   Pd(dppf)Cl₂        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(PPh₃)₄ palladium(0)tetrakis(triphenylphosphine)    -   Ph₃P═O triphenylphosphine oxide    -   t-Bu or Bu^(t) tert-butyl    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   Zn (CN)₂ zinc cyanide

IV. Synthesis

The compounds of the present disclosure can be prepared in a number ofways known to one skilled in the art of organic synthesis in view of themethods, reaction schemes and examples provided herein. The compounds ofthe present disclosure can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the disclosure

The starting materials are generally available from commercial sourcessuch as Aldrich Chemicals (Milwaukee, Wis.) or are readily preparedusing methods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), Larock,R. C., Comprehensive Organic Transformations, 2^(nd)-ed., Wiley-VCHWeinheim, Germany (1999), or Beilsteins Handbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, Berlin, including supplements (alsoavailable via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the presentdisclosure as well as key intermediates. For a more detailed descriptionof the individual reaction steps, see the Examples section below. Thoseskilled in the art will appreciate that other synthetic routes may beused to synthesize the inventive compounds. Although specific startingmaterials and reagents are depicted in the schemes and discussed below,other starting materials and reagents can be easily substituted toprovide a variety of derivatives and/or reaction conditions. Inaddition, many of the compounds prepared by the methods described belowcan be further modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

In the preparation of compounds of the present disclosure, protection ofremote functionality of intermediates may be necessary. The need forsuch protection will vary depending on the nature of the remotefunctionality and the conditions of the preparation methods. The needfor such protection is readily determined by one skilled in the art. Fora general description of protecting groups and their use, see Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Ed., Wiley(2007). Protecting groups incorporated in making of the compounds of thepresent disclosure, such as the trityl protecting group, may be shown asone regioisomer but may also exist as a mixture of regioisomers.

Scheme 1 (below) describes potential routes for producing the compoundsof the present disclosure which include compounds of Formula (IA).Compounds of Formula (IA) can be made substantially optically pure byeither using substantially optically pure starting material or byseparation chromatography, recrystallization or other separationtechniques well-known in the art. For a more detailed description, seethe Example section below.

Under Scheme 1, the 5-chloro- or 5-bromo-substituted4-chloro-2-(methylthio)pyrimidine 1 was treated with hydrazine to formthe 5-chloro- or 5-bromo-substituted4-hydrazinyl-2-(methylthio)pyrimidine 2, which was transformed to thecyclized product 3 upon treatment with trimethyl orthoformate ortriethyl orthoformate. Subsequently, 3 was treated with appropriateamine to generate 4, which was followed by cross-coupling reaction withappropriate R³ reagent (e.g., various boronic acid or equivalent withappropriate R³ group) to afford product 5.

Alternatively, in some cases, compounds of the present invention wereprepared according to the reaction sequence in Scheme 2. Compound 4 wasfirst protected as 4′ and then followed by coupling reaction to add R³group to afford compound 5′. Final compound 5 was obtained after properdeprotection of compound 5′. For a general description of protectinggroups and their use, see Greene, T. W. et al., Protecting Groups inOrganic Synthesis, 4th Ed., Wiley (2007).

General Methods

The following methods were used in the exemplified Examples, exceptwhere noted otherwise.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and ethyl acetate or DCM and MeOHunless otherwise indicated. For highly polar amines, gradients of DCMand 1 M NH₃ in MeOH were used. Reverse phase preparative HPLC wascarried out using C18 columns with UV 214 nm and 254 nm or prep LC-MSdetection eluting with gradients of Solvent A (water with 0.1% TFA) andSolvent B (acetonitrile with 0.1% TFA) or with gradients of Solvent A(water with 0.05% TFA) and Solvent B (acetonitrile with 0.05% TFA) orwith gradients of Solvent A (water with 0.05% ammonia) and Solvent B(acetonitrile with 0.05% ammonia).

LC/MS Methods Employed in Characterization of Examples

Reverse phase analytical HPLC/MS was performed on Agilent LC1200 systemscoupled with 6110 (Methods A-D), or 6120 (Method E and F), or 6130(Method G) Mass Spectrometer.

-   Method A: Linear gradient of 5% to 95% B over 1.2 min, with 1 min    hold at 95% B;    -   UV visualization at 214 nm and 254 nm    -   Column: SunFire® C18 4.6×50 mm 3.5 μm    -   Flow rate: 2 mL/min    -   Solvent A: 0.1% trifluoroacetic acid, 99.9% water    -   Solvent B: 0.1% trifluoroacetic acid, 99.9% acetonitrile.-   Method B: Linear gradient of 5% to 95% B over 1.5 min, with 1 min    hold at 95% B;    -   UV visualization at 214 nm and 254 nm    -   Column: XBridge® C18 4.6×50 mm 3.5 μm    -   Flow rate: 2 mL/min    -   Solvent A: water with 10 mM Ammonium hydrogen carbonate    -   Solvent B: acetonitrile.-   Method C: Linear gradient of 5% to 95% B over 1.2 min, with 1.3 min    hold at 95% B, 95% to 5% B over 0.01 min;    -   UV visualization at 214 nm and 254 nm    -   Column: SunFire® C18 4.6×50 mm 3.5 μm    -   Flow rate: 2 mL/min    -   Solvent A: 0.1% trifluoroacetic acid, 99.9% water    -   Solvent B: 0.1% trifluoroacetic acid, 99.9% acetonitrile.-   Method D: Linear gradient of 5% to 95% B over 1.4 min, with 1.6 min    hold at 95% B, 95% to 5% B over 0.01 min;    -   UV visualization at 214 nm and 254 nm    -   Column: XBridge® C18 4.6×50 mm 3.5 μm    -   Flow rate: 1.8 mL/min    -   Solvent A: water with 10 mM Ammonium hydrogen carbonate    -   Solvent B: acetonitrile.-   Method E: Linear gradient of 5% to 95% B over 1.5 min, with 1 min    hold at 95% B; UV visualization at 214 nm and 254 nm    -   Column: XBridge® C18 4.6×50 mm 3.5 μm    -   Flow rate: 2 mL/min    -   Solvent A: water with 10 mM Ammonium hydrogen carbonate    -   Solvent B: acetonitrile.-   Method F: Linear gradient of 5% to 95% B over 1.5 min, with 1 min    hold at 95% B;    -   UV visualization at 214 nm and 254 nm and 300 nm    -   Column: XBridge® C18 4.6×30 mm 2.5 μm    -   Flow rate: 1.8 mL/min    -   Solvent A: water with 0.1% ammonia    -   Solvent B: acetonitrile.-   Method G: Linear gradient of 10% to 95% B over 2 min, with 1 min    hold at 95% B;    -   UV visualization at 214 nm, 254 nm and 300 nm    -   Column: Sunfire® C18 4.6×30 mm 2.5 μm    -   Flow rate: 1.8 mL/min    -   Solvent A: water    -   Solvent B: MeOH with 0.1% formic acid.

NMR Employed in Characterization of Examples

¹H NMR spectra were obtained with Bruker Fourier transform spectrometersoperating at frequencies as follows: ¹H NMR: 400 MHz (Bruker). ¹³C NMR:100 MHz (Bruker). Spectra data are reported in the format: chemicalshift (multiplicity, number of hydrogens). Chemical shifts are specifiedin ppm downfield of a tetramethylsilane internal standard (6 units,tetramethylsilane=0 ppm) and/or referenced to solvent peaks, which in ¹HNMR spectra appear at 2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, 1.94for CD₃CN, and 7.24 ppm for CDCl3, and which in ¹³C NMR spectra appearat 39.7 ppm for CD₃SOCD₃, 49.0 ppm for CD₃OD, and 77.0 ppm for CDCl₃.All ¹³C NMR spectra were proton decoupled.

V. Examples

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following examples demonstrate apartial scope of the disclosure and are not meant to be limiting of thescope of the disclosure.

Unless specified otherwise, starting materials are generally availablefrom a non-excluding commercial sources such as TCI Fine Chemicals(Japan), Shanghai Chemhere Co., Ltd. (Shanghai, China), Aurora FineChemicals LLC (San Diego, Calif.), FCH Group (Ukraine), AldrichChemicals Co. (Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham,N.H.), Acros Organics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd.(Cornwall, England), Tyger Scientific (Princeton, N.J.), AstraZenecaPharmaceuticals (London, England), Chembridge Corporation (USA), MatrixScientific (USA), Conier Chem & Pharm Co., Ltd (China), Enamine Ltd(Ukraine), Combi-Blocks, Inc. (San Diego, USA), Oakwood Products, Inc.(USA), Apollo Scientific Ltd. (UK), Allichem LLC. (USA) and UkrorgsyntezLtd (Latvia). PharmaBlock R&D Co. Ltd (Nanjing, China), Accela ChemBioCo. Ltd (Shanghai, China), Alputon Inc. (Shanghai, China), J&KScientific Ltd. (Beijing, China).

INTERMEDIATES Intermediate 3:8-bromo-5-(methylthio)-[1,2,4]triazolo[4,3-c]pyrimidine

5-Bromo-4-hydrazinyl-2-(methylthio)pyrimidine (2): To a solution of5-bromo-4-chloro-2-(methylthio)pyrimidine (1, 49.0 g, 0.205 mol) inethanol (1000 mL) was added hydrazine (21.5 g, 0.430 mol). The reactionwas stirred at rt for 4 h. The resulting suspension was filtered, washedwith hexane and dried in vacuum to give the title compound (44.1 g, 92%)as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.42 (s, 3H), 8.08 (s,1H). LC-MS: [M+H]⁺=234.9; 236.9.

Intermediate 3: 5-bromo-4-hydrazinyl-2-(methylthio)pyrimidine (2) (40.0g, 0.17 mol) was dissolved in 200 mL triethoxymethane. The mixture washeated at reflux and stirred for 3 h. The reaction mixture wasconcentrated under reduced pressure, the residue was purified by flashchromatography (EA:PE=1:15-1:1) to give the title compound (38.3 g, 92%)as a white solid. ¹H-NMR (400 MHz, methanol-d₄) δ ppm 2.82 (s, 3H), 8.03(s, 1H), 8.87 (s, 1H). LC-MS: [M+H]⁺=245.0; 247.0.

Intermediate A1:8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

2-Bromo-4-(2,2-diethoxyethoxy)-1-fluorobenzene (A1.1): To a solution of3-bromo-4-fluorophenol (500 g, 2.62 mol) and 2-bromo-1,1-diethoxyethane(670 g, 3.4 mol) in 2.0 L DMF was added K₂CO₃ (1085 g, 7.86 mol) in oneportion. The suspension was heated at 110° C. and stirred overnightunder N₂. After cooling to rt, the reaction was diluted with 10.0 L H₂O,and extracted with EtOAc (2.0 L×3). The combined organic phase waswashed with brine twice, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on silicagel (EtOAc/hexane=0:100 to 5:100) to give the title compound (810 g,80%) as a yellow oil. ¹H-NMR (400 MHz, methanol-d4) δ ppm 1.27 (t, 6H),3.65 (q, 2H), 3.78 (q, 2H), 3.97 (d, 2H), 4.82 (t, 1H), 3.97 (d, 2H),6.84 (dd, 1H), 7.04 (dd, 1H), 7.13 (d, 1H).

4-Bromo-5-fluorobenzofuran (A1.2a along with regioisomer A1.2b): To asolution of PPA (1324 g, 3.93 mol) in toluene (2.0 L) was add A1.1 (810g, 2.62 mol) over 30 min at 95° C. The reaction mixture was stirred at95° C. for 2 h. After cooling to rt, 4.0 L ice-water was added slowly.The mixture was extracted with PE (2.0 L×2), the combined organic phasewas washed with brine (2.0 L×2), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified onsilica gel (EtOAc/PE=0:100 to 5:100) to give a mixture of A1.2a andA1.2b (A1-2a: A1-2b=1:0.7, 310 g, 55% yield) as a yellow oil.

5-Fluorobenzofuran-4-carbonitrile (A1.3): To a mixture of A1.2a andA1.2b (310 g, 1.44 mol) and Zn (CN)₂ (253 g, 2.16 mol) in 1.0 L DMF wasadded Pd(PPh₃)₄ (162 g, 0.14 mol) under N₂. The reaction mixture washeated at 100° C. and stirred for 18 h. After cooling to rt, the mixturewas diluted with 5.0 L of water, and extracted with EtOAc (1.0 L×2). Thecombined organic phase was washed with brine (1 L), dried over Na₂SO₄(anhydrous), filtered and concentration under reduced pressure. Theresidue was purified by flush column (mobile phase: EtOAc/PE=1:70 in 30min, Ret. Time=11 min, flow rate:120 mL/min) to give the title compound(92 g, 40%) as a white solid. ¹H-NMR (400 MHz, methanol-d₄) δ ppm 7.07(d, 1H), 7.30 (dd, 1H), 7.89 (dd, 1H), 8.10 (dd, 1H).

tert-Butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate(A1.4): To a solution of A1.3 (44.5 g, 276.4 mmol) and Boc₂O (90.0 g,414.6 mmol) in 1.0 L MeOH was added Pd/C (5 g, 10% wt). The reactionmixture was degassed with H₂ and stirred under H₂ overnight. The mixturewas filtered through celite, washed with MeOH (300 mL×2), the filtratewas concentrated under reduced pressure. The residue was recrystallizedfrom PE to give the title compound (61.0 g, 93%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (s, 9H), 3.21 (t, 2H), 4.12 (d,2H), 4.53 (t, 2H), 6.63 (dd, 1H), 6.86 (dd, 1H), 7.25 (br s, 1H). LC-MS:[M-^(t)Bu+H]⁺=212.1.

(5-Fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (A1.5): A solution ofA1.4 (18.3 g, 68.5 mmol) in 50 mL HCl/Dioxane (4 mol/L) was stirred atrt for 4 h. The mixture was concentrated under reduced pressure. Theresidue was diluted with a mixture solvent (MeOH:MeCN=1:10, 500 mL),then K₂CO₃ (18.0 g, 342.5 mmol) was added. The mixture was heated at 60°C. and stirred for 3 h, cooled to rt, filtered, and concentrated underreduced pressure. The crude product was purified on silica gel(MeOH:EtOAc=0:100 to 1:4) to give the title compound (9.2 g, 80%) as ayellow oil. ¹H-NMR (400 MHz, methanol-d₄) δ ppm 3.27 (t, 2H), 3.77 (s,2H), 4.56 (t, 2H), 6.59 (dd, 1H), 6.81 (dd, 1H). LC-MS: [M+H]⁺=168.1.

Intermediate A1: A mixture of A1.5 (1.41 g, 8.2 mmol) and8-bromo-5-(methylthio)-[1,2,4]triazolo[4,3-c]pyrimidine (3) (1.0 g, 4.1mmol) was heated at 40° C. and stirred for 16 h. After cooling to thert, the mixture was diluted with EtOAc (35 mL). The precipitate wasfiltered and washed with EtOAc (3 mL×3), dried in vacuum to give thetitle compound (1.0 g, 67%) as a white solid. ¹H NMR (500 MHz, DMSO) δppm 3.27 (t, 2H), 4.53 (t, 2H), 4.66 (d, 2H), 6.71 (dd, 1H), 6.95 (t,1H), 7.85 (s, 1H), 8.75 (t, 1H), 9.48 (s, 1H). LC-MS: [M+H]⁺=363.7;365.7.

Intermediate A2:8-bromo-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(2,3-dihydrobenzofuran-4-yl)methanamine A2.3

(E)-Benzofuran-4-carbaldehyde oxime (A2.1): A mixture ofbenzofuran-4-carbaldehyde (5 g, 34.2 mmol), NH₂OH.HCl (4.72 g, 68.4mmol) and NaOH (5.47 g, 136.8 mmol) in CH₃OH (75 mL), and water (75 mL)was heated to 25° C. and stirred for 3 h. The mixture was concentrated,the residue was diluted with EA (150 ml), the organic layer was washedsuccessively with 1N HCl (100 mL×2), sat. NaHCO₃ (100 mL×2) and brine(100 mL), dried over Na₂SO₄, filtered and concentrated to give the titlecompound (5 g, 90%) as a white solid. LC-MS: [M+H]⁺=162.0.

Benzofuran-4-ylmethanamine (A2.2): A mixture of A2.1 (5 g, 31 mmol),NH₄.OH (43 mL) and Raney Ni (2.66 g, 31 mmol) in CH₃OH (585 mL) wasstirred at 20° C. for 16 h under H₂ atmosphere. The mixture wasfiltered, and the filtrate was concentrated to give the title compound(4.2 g, 92%) as oil. LC-MS: [M+H]⁺=148.1.

(2,3-Dihydrobenzofuran-4-yl)methanamine (A2.3): A mixture of A2.2 (2.2g, 15 mmol), Pd/C (2 g, wt %:10%) and CH₃OH (40 mL) was heated to 48° C.and stirred for 16 h under N₂ atmosphere. The mixture was cooled to rt,filtered, and the filtrate was concentrated to give the title compound(2 g, 90%). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.20 (t, 2H), 3.84 (s, 2H),4.60 (t, 2H), 6.72 (d, 1H), 6.85 (d, 1H), 7.13 (t, 1H).

Intermediate A2: The title compound was prepared by a method similar tothat of A1 by replacing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine(A1.5) with A2.3. ¹H NMR (400 MHz, DMSO) δ ppm 3.19 (t, 2H), 4.50 (t,2H), 4.64 (s, 2H), 6.68 (d, 1H), 6.84 (d, 1H), 7.05 (t, 1H), 7.81 (s,1H), 9.48 (s, 1H). LC-MS: [M+H]⁺=346.0.

Intermediate A3:8-Bromo-N-((2-methyl-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

Methyl 2-(prop-2-yn-1-yloxy)benzoate (A3.1): To a solution of methyl2-hydroxybenzoate (3.0 g, 19.72 mmol) in DMF (20 mL) was added3-bromoprop-1-yne (6 mL, 19.72 mmol) and K₂CO₃ (8.18 g, 59.2 mmol). Themixture was sitted at 20° C. overnight, diluted with DCM and washed withwater (80 mL×3). The organic layer was dried with Na₂SO₄ andconcentrated. The residue was purified with flash chromatography,triturated by EA/Hexane=10% to give the title compound (3.0 g, 90%).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.53 (s, 1H), 3.90 (s, 3H), 4.10 (s, 2H),7.06 (t, 1H), 7.15 (d, 1H), 7.48 (t, 1H), 7.82 (d, 1H). LC-MS:[M+H]⁺=190.9.

Methyl 2-methylbenzofuran-7-carboxylate (A3.2): A mixture of A3.1 (1.0g, 5.26 mmol) and cesium fluoride (1.038 g, 6.84 mmol) inN,N-diethylaniline (5 mL, 5.26 mmol) was irritated by microwave at 200°C. for 30 min. After diluted with ether insoluble materials were removedby decantation. The crude products were separated on columnchromatography by using a mixed solvent of hexane and ethyl acetate(10:1, v/v) to give the title compound (500 mg, 50%). ¹H NMR (400 MHz,CDCl₃) δ ppm 2.55 (s, 3H), 4.01 (s, 3H), 6.44 (s, 1H), 7.22-7.27 (m,1H), 7.66 (d, 1H), 7.86 (d, 1H). LC-MS: [M+H]⁺=191.0.

(2-Methylbenzofuran-7-yl)methanol (A3.3): A solution of A3.2 (1.0 g,5.26 mmol) in THF (3 mL) was added LiAlH₄ (10.52 mL, 10.52 mmol). Themixture was stirred for 1 h at 0° C. and warmed to rt for 2 h, quenchedwith 1M HCl solution and filtered, concentrated to give the titlecompound as the crude product, which will be used in next step withoutfurther purification.

4-(Azidomethyl)-2-methylbenzofuran (A3.4): To a stirred solution of A3.3(350 mg, 2.158 mmol) in toluene (10 mL) was added DPPA (683 mg, 2.482mmol). The reaction mixture was cooled to 0° C., and DBU (0.390 mL, 2.59mmol) was added dropwise. The reaction mixture was allowed to warm tort, and stirred under N₂ overnight. The mixture was adjusted to pH=5-6by 1N HCl, then extracted with EtOAc. The water phase was neutralized bysat. NaHCO₃, then extracted with EtOAc. The combined organic phase waswashed successively with NaHCO₃ and brine, dried, and concentrated, theresidue was purified by column chromatography (5% EtOAc in hexane aseluent) to afford the title compound (200 mg, 50%) as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.49 (s, 3H), 4.64 (s, 2H),7.15-7.17 (m, 2H), 7.45-7.48 (m, 1H).

(2-methylbenzofuran-4-yl)methanamine (A3.5): To a solution of A3.4 (50mg, 0.267 mmol) in THF (5 mL) and Water (0.2 mL) was added PPh₃ (140 mg,0.534 mmol). The mixture was stirred at 25° C. for 2 h, concentratedunder reduced pressure, the residue was purified with flashchromatography to give the title compound (30 mg, 70%) as a colorlessoil. (The Ph₃P═O and PPh₃ came out in 50% PE/EA and the amine came outin 20% DCM/MeOH). LC-MS: [M+H]⁺=162.1.

(2-Methyl-2,3-dihydrobenzofuran-4-yl)methanamine (A3.6): To a solutionof A3.5 (100 mg, 0.372 mmol) in Methanol (10 mL) was added Hydrochloricacid (0.1 mL, 3.29 mmol) and Pd/C (10%) (39.6 mg). The reaction wasstirred at 50° C. for 12 h under hydrogen atmosphere, filtered and theconcentrated. The residue was purified with flash chromatography(DCM:MeOH=10:1) to afford the title compound (60 mg, 50%). ¹H NMR (400MHz, MeOD) δ ppm 1.41-1.47 (m, 3H), 2.76-2.91 (m, 1H), 4.05 (s, 2H),4.93-5.00 (m, 2H), 6.74-6.79 (m, 1H), 6.88 (d, 2H), 7.16-7.18 (m, 1H).LC-MS: [M+H]⁺=164.1.

Intermediate A3: The title compound was prepared by a method similar tothat of Intermediate A1 by replacing(5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (A1.5) with A3.6. ¹HNMR (Methanol-d₄) 5: 1.40-1.47 (m, 3H), 2.75-2.90 (m, 1H), 3.35-3.44 (m,1H), 4.71 (d, 2H), 4.93-4.98 (m, 1H), 6.63-6.79 (m, 1H), 6.87-6.90 (m,1H), 7.04-7.16 (m, 1H), 7.86 (d, 1H), 9.30 (d, 1H). LC-MS: [M+H]⁺=359.7.

Intermediate B (boronic acid or ester that are not commerciallyunavailable for synthesis of compounds in table 2)

2,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(B1)

5-Bromo-2,6-dimethylpyrimidin-4-ol (B1.1): Bromine (153.4 g, 0.96 mol,1.2 eq) was added dropwise to a solution of 2,6-dimethylpyrimidin-4-ol(100 g, 0.8 mol, 1.0 eq) in 1.0 L of chloroform. Then the mixture wasstirred at 50° C. overnight. After cooling to rt, excess solvent wasevaporated and 500 mL of ethyl acetate was added, which was removedunder reduced pressure again. This process was repeated three times. Theyellow solid was stirred in 100 mL of ethyl acetate for 30 min at rt.After filtration, the residue was washed with ethyl acetate (100 mL×2)to give the title compound (135 g, 82%) as a white solid. LC-MS:[M+H]⁺=205.2.

5-Bromo-4-chloro-2,6-dimethylpyrimidine (B1.2): A mixture of B1.1 (134g, 0.66 mol) in 500 mL of POCl₃ was stirred at 110° C. for 18 h. ExcessPOCl₃ was removed under vacuum, the residue was poured into 1000 gcrushed ice. Then solid NaHCO₃ was added carefully to adjust pH to 8-9.The aqueous was extracted with ethyl acetate (1.5 L×3), and the combinedorganic layers were washed with brine (1.0 L×2), dried over Na₂SO₄,concentrated to give the title compound (71 g, 48%) as a white solid.LC-MS: [M+H]⁺=223.0.

5-Bromo-4-hydrazinyl-2,6-dimethylpyrimidine (B1.3): To a mixture ofHydrazine hydrate (NH2NH2.H2O, 32 g, 0.64 mol, 98%) in 350 mL ethanolwas added a solution of B1.2 (70 g, 0.32 mol) in 350 mL methanoldropwise at 0° C. The reaction mixture was stirred at rt for 16 h. Thesolvent was removed by reduced pressure, the residue was diluted with500 mL of water, extracted with CHCl₃ (500 mL×3). The combined organiclayers were washed with 500 mL brine, dried over Na₂SO₄, andconcentrated to give the title compound (63 g, 91%) as a yellow solid.LC-MS: [M+H]⁺=219.0.

5-Bromo-2,4-dimethylpyrimidine (B1.4): To a suspension of MnO₂ (96 g,1.1 mol) in 1.0 L CHCl₃ was added a solution of B1.3 (47 g, 0.22 mol) in1.0 L CHCl₃ dropwise at 0° C. The mixture was stirred for 2 h at rt.After filtration and concentration, the residue was purified on 100-200mesh silica gel column (PE:EA=100:0 to 50:50) to give the title compound(30 g, 73%) as a yellow solid. LC-MS: [M+H]⁺=189.1.

Intermediate B1: A mixture of B1.4 (12 g, 64 mmol),bis(pinacolato)diboron (22.8 g, 89.6 mmol, 1.4 eq), KOAc (18.8 g, 192mmol, 3.0 eq), and Pd(dppf)Cl₂ (2.34 g, 3.2 mmol) in 200 mL of anhydrousdioxane was heated at 90° C. and stirred for 4 h under N₂. The solventwas removed under reduced pressure, the residue was diluted with 300 mLmixed solvent (PE:EA=4:1), filtered and concentrated. The crude productwas purified by flash column chromatography (PE:EA=2:1 to 1:1) to givethe title compound (10 g, 66%) as a yellow oil. LC-MS: [M+H]⁺=235.1.

Intermediate B2: (1-Isopropyl-3-methyl-1H-pyrazol-4-yl)boronic acid

4-Bromo-1-isopropyl-3-methyl-1H-pyrazole (B2.1): A mixture of4-bromo-3-methyl-1H-pyrazole (2 g, 12.5 mmol), 2-iodopropane (6.37 g,37.5 mmol), Cs₂CO₃ (6.25 g, 50 mmol) and acetonitrile (30 mL) wasstirred at 90° C. for 12 h. The reaction mixture was filtered with MeOH(15 ml) and the filtrate was concentrated. The residue was purified byflash chromatography on silica gel (UV214, PE:DMC=100:1 to 50:50) toafford the title compound (700 mg, 56%) as a clear oil. LC-MS:[M+H]⁺=203.1.

Intermediate B2: To a solution of B2.1 (202 mg, 1.0 mmol) in THF (5 mL)was added n-BuLi (0.5 mL, 1.2 mmol, 2.4 M in THF) under N₂ at −78° C.The reaction was stirred at −78° C. for 30 min, and then triisopropylborate (564 mg, 3.0 mmol) in THF (2 mL) was added dropwise with stirringon at −78° C. The mixture was stirred at −78° C. for 2 h. The mixturewas quenched with water (3 mL), the aqueous layer was purified by flashchromatography (silica gel, UV214, NH₄HCO₃\water\MeOH=0.51001) to givethe title compound (100 mg, 60%) as a white solid. LC-MS: [M+H]⁺=169.1.

Intermediate B3:2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-methoxy-4-methylpyridine (B3.1): Sodium (4.8 g, 0.2 mol) wasadded to a stirred solution of 80 mL CH₃OH portion by portion. Afteraddition, 5-bromo-2-fluoro-4-methylpyridine (7.6 g, 40 mmol) was addedsubsequently by neat. Then the clear solution was stirred at rtovernight. The reaction was quenched by water (400 mL), extracted withdichloromethane (300 mL×3). The combined organic phase was washed withbrine, dried over sodium sulphate, filtered and concentrated to give thetitle compound (6.95 g, 86%) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃) b 2.31 (s, 3H), 3.87 (s, 3H), 6.61 (s, 1H), 8.15 (s, 1H).

Intermediate B3: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B3.1. LC-MS:[M+H]⁺=250.1.

Intermediate B4:6-cyclopropyl-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-6-cyclopropyl-2-methylpyridine (B4.1): A mixture of3,6-dibromo-2-methylpyridine (250 mg, 1 mmol), cyclopropylboronic acid(86 mg, 1 mmol), Cs₂CO₃ (975 mg, 3 mmol), Pd(PPh₃)₄ (160 mg, 0.2 mmol)and dioxane (5 mL) was stirred at 120° C. under N₂ with microwave for 30min. The mixture was filtered with MeOH (15 mL), the filtrate waspurified by Prep-TLC (silica gel, UV254, PE) to afford the titlecompound (100 mg, 47%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ ppm0.95-0.98 (m, 4H), 1.36-1.99 (m, 1H), 2.56 (s, 3H), 6.76 (d, 1H), 7.59(d, 1H).

Intermediate B4: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B4.1. LC-MS:[M+H]⁺=260.3.

Intermediate B5:2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromopicolinaldehyde (B5.1): A mixture of 3-bromo-2-methylpyridine (5g, 29 mmol), SeO₂ (17.5 mg, 116 mmol) in dioxane (70 mL) was heated to120° C. and stirred for 18 h. The mixture was concentrated and purifiedby silica gel (PE:EA=4:1) to give the title compound (3 g, 55%) as awhite solid. LC-MS: [M+H]⁺=188.1.

(3-Bromopyridin-2-yl)methanol (B5.2): To a mixture of B5.1 (1 g, 5.4mmol) in MeOH (20 mL) and THF (10 mL) was cooled to 0° C., NaBH₄ (0.82g, 21.6 mmol) was added in portions. The mixture was stirred for 4 h atrt. The mixture was concentrated, diluted with water (40 mL), extractedwith DCM (40 mL×3), the organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated to give the title compound (1 g, 99%)as a white solid. LC-MS: [M+H]⁺=190.0.

3-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (B5.3): Amixture of B5.2 (1 g, 5.4 mmol), DMAP (0.33 g, 1.08 mmol), TBSCI (0.97g, 6.48 mmol) and imidazole (0.48 g, 7 mmol) in DCM (30 mL) was stirredfor 18 h at rt. The mixture was diluted with DCM (50 mL), washed withwater (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered andconcentrated, the residue was purified on silica gel (PE:EA=100:0 to50:50) to give the title compound (1.1 g, 68%) as a colorless oil.LC-MS: [M+H]⁺=304.0.

Intermediate B5: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B5.3. LC-MS:[M+H]⁺=350.1.

IntermediateB6:1,3,5-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(10 g, 45 mmol), iodomethane (9.6 g, 67.5 mmol), K₂CO₃ (15.5 g, 112.5mmol) in acetone (50 mL) was stirred at 60° C. for 12 h. The reactionmixture was filtered, washed with MeOH (35 ml), the filtrate wasconcentrated to afford the title compound (8 g, 75%) as a white solid.LC-MS: [M+H]⁺=237.2.

Intermediate B7:2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-2-(difluoromethyl)pyridine (B7.1): To a solution of3-bromopicolinaldehyde (B5.1) (3.0 g, 16.1 mmol) in DCM (20 mL) wasadded DAST (5.2 g, 32.2 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 2 h under N₂, then NaHCO₃ solution was added under icebath. The mixture was extracted with DCM (60 mL), the organic layer wasdried and concentrated. The residue was purified by flash chromatographyto give the title compound (2.5 g, 75%) as a gray solid, which was usedin the next step without further purification.

Intermediate B7: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B7.1. The crude productwas used in the next step without further purification.

Intermediate B8:2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

2-Cyclopropyl-6-methylpyrimidin-4-ol (B8.1): A mixture ofcyclopropane-carboximidamide hydrochloride (2.0 g, 16.7 mmol), methyl3-oxobutanoate (1.9 g, 16.7 mmol) and CH₃ONa (1.8 g, 33.4 mmol) in MeOH(200 mL) was stirred at rt for 18 h. Then the mixture was diluted withSat. Na₂SO₃ (50 mL), then concentrated under reduced pressure. Theresidue was dissolved in 50 mL water, adjusted pH to 4. After cooling to5° C., the solid was collected and dried in vacuum to give the titlecompound (2.0 g, 98%) as a yellow solid. The crude product was used inthe next step without further purification. LC-MS: [M+H]⁺=151.2.

5-Bromo-2-cyclopropyl-6-methylpyrimidin-4-ol (B8.2): A mixture of B8.1(2.0 g, 13.3 mmol) and KOH (744 mg, 13.3 mmol) in H₂O (15 mL) was addedBr₂ (0.7 mL) at 0° C. The reaction mixture was stirred at rt for 2 h.The solid was filtered to give the title compound (1.5 g, 57%) as awhite solid. The crude product was used in the next step without furtherpurification. LC-MS: [M+H]⁺=231.0.

5-Bromo-4-chloro-2-cyclopropyl-6-methylpyrimidine (B8.3): A mixture ofB8.2 (1.5 g, 6.55 mmol) and DMF (1.26 mL, 16.38 mmol) in Toluene (20 mL)was added dropwise a solution of POCl₃ (0.72 mL) in Toluene (5 mL) at 0°C. The reaction mixture was stirred at rt for 3 h, then poured intoNa₂CO₃ (1M, 30 mL), extracted with EA (20 mL×3). The combined organicphase was concentrated to give the title compound (1.0 g, 62%) as ayellow oil. The crude product was used in the next step without furtherpurification. LC-MS: [M+H]⁺=248.9.

N′-(5-Bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide(B8.4): A mixture of B8.3 (1.0 g, 4.06 mmol),4-methylbenzenesulfonohydrazide (2.6 g, 13.8 mmol) in CHCl₃ (50 mL) wasstirred at 90° C. for 16 h. The solid was filtered and washed with DCM(5 mL) to give the title compound (0.60 g, 37.5%) as a white solid. Thecrude product was used in the next step without further purification.LC-MS: [M+H]⁺=397.0.

5-Bromo-2-cyclopropyl-4-methylpyrimidine (B8.5): A mixture of B8.4 (600mg, 1.51 mmol) in Na₂CO₃ (8 mL, 4.53 mmol) was stirred at 90° C. for 1h. The mixture was diluted with EA (20 mL). The organic phase wasseparated and concentrated to give the title compound (200 mg, 62%) as abrown oil. The crude product was used in the next step without furtherpurification. LC-MS: [M+H]⁺=213.0.

Intermediate B8: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B8.5. The crude productwas used in the next step without further purification. LC-MS:[M+H]⁺=261.2.

Intermediate B9: (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)boronicacid

4-Bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (B9.1): The titlecompound was prepared by a method similar to that of B7.1 by replacing3-bromopicolinaldehyde (B5.1) with4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde. ¹H NMR (400 MHz, CDCl₃) bppm 3.91 (s, 3H), 6.66 (t, 1H), 7.43 (s, 1H). LC-MS: [M+H]⁺=213.1.

Intermediate B9: The title compound was prepared by a method similar tothat of Intermediate B2 by replacing4-bromo-1-isopropyl-3-methyl-1H-pyrazole (B2.1) with B9.1. LC-MS:[M+H]⁺=177.2.

Intermediate B10:2-isopropoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

5-Bromo-2-isopropoxy-4-methylpyrimidine (B10.1): To a solution of5-bromo-2-chloro-4-methylpyrimidine (3.0 g, 14.5 mmol) in THF (30 mL)was added NaH (1.74 g, 44 mmol), it was stirred at rt for 0.5 h. Thenpropan-2-ol (2.6 g, 44 mmol) was added, the mixture was stirred at rtfor 3 h. The mixture was concentrated, the residue was diluted withwater (20 mL), extracted with EA (20×3 mL). The organic layer was driedand concentrated, the crude product was purified by flash chromatography(silica gel; EA:PE=1:4) to give the title compound (2.8 g, 83%)) as agray solid. LC-MS: [M+H]⁺=231.0; 232.9.

Intermediate B10: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B10.1. LC-MS:[M+H]⁺=279.3.

Intermediate B11:2-(Difluoromethoxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-(difluoromethoxy)-4-methylpyridine (B11.1): To a solution of5-bromo-4-methylpyridin-2-ol (8 g, 42.55 mmol) and2,2-difluoro-2-(fluorosulfonyl)acetic acid (9.1 g, 51.06 mmol) in 40 mLCH₃CN was added Na₂SO₄ (606 mg, 4.255 mmol) in one portion. Thesuspension was stirred at rt overnight, then concentrated under vacuum,the residue was purified on silica gel (PE/EtOAc=0-9%) to give the titlecompound (500 mg, 37%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 2.39(s, 3H), 7.19 (s, 1H), 7.51-7.80 (m, 1H), 8.39 (s, 1H). LC-MS:[M+H]⁺=239.9.

Intermediate B11: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B11.1. LC-MS:[M+H]⁺=286.2.

Intermediate B12:1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pyrrolidin-2-one

1-(5-Bromopyridin-3-yl)pyrrolidin-2-one (B12.1): A mixture of3,5-dibromopyridine (500 mg, 2.1 mmol), pyrrolidin-2-one (170 mg, 2.0mmol), K₂CO₃ (1.04 g, 7.56 mmol), CuI (4 mg, 0.021 mmol),N1,N1,N2,N2-tetramethylethane-1,2-diamine (3 mg, 0.021 mmol) and dioxane(10 mL) was stirred at 110° C. for 12 h. 30 mL of H₂O was added to themixture and extracted with ethyl acetate (20 mL×3). The combined organiclayers was washed with water (25 mL×3) and brine (20 mL×3), dried overNa₂SO₄, concentrated and purified by flash chromatography (silica gel,40 g, UV254, PE\EA=100\1 to 2\1) to give the title compound (240 mg,47%) as a gray solid. LC-MS: [M+H]⁺=243.1.

Intermediate B12: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B12.1. LC-MS:[M+H]⁺=206.2.

Intermediate B13:3-(3-(methylsulfonyl)propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-5-(3-bromopropoxy)pyridine (B13.1): A mixture of5-bromopyridin-3-ol (500 mg, 2.87 mmol), 1,3-dibromopropane (870 mg,4.31 mmol), NaH (230 mg, 5.74 mmol) and DMF (10 mL) was stirred at 0° C.for 12 h. The mixture was added water (10 mL), extracted with EA (10mL×3), the extracts were washed with water (25 mL×3) and brine (20mL×3), dried over Na₂SO₄, concentrated and purified by flashchromatography (silica gel, 40 g, PE/EA=100/1 to 2/1) to give the titlecompound (300 mg, 36%) as a gray solid. LC-MS: [M+H]⁺=296.0.

3-Bromo-5-(3-(methylsulfonyl)propoxy)pyridine (B13.2): A mixture ofB13.1 (300 mg, 1.02 mmol), NaOSOCH₃ (156 mg, 1.53 mmol), and DMSO (2 mL)was stirred at rt overnight. 10 mL water was added to the mixture,extracted with ethyl acetate (10 mL×3), the organis layers were washedwith water (25 mL×3) and brine (20 mL×3), dried over Na₂SO₄,concentrated and purified by flash chromatography (silica gel, 40 g,UV254, PE\EA=100\1 to 2\1) to give the title compound (120 mg, 40%) as agray solid. LC-MS: [M+H]⁺=294.0.

Intermediate B13: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B13.2. The crude productwas used in the next step without further purification. LC-MS:[M+H]⁺=260.1.

Intermediate B14:3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxazolidin-2-one

3-(5-Bromopyridin-2-yl)oxazolidin-2-one (B14.1): A mixture of2,5-dibromopyridine (1.0 g, 4.21 mmol), pyrrolidin-2-one (1.1 g, 12.7mmol), K₂CO₃ (1.16 g, 8.42 mmol), CuI (40 mg, 0.21 mmol),N1,N1,N2,N2-tetramethylethane-1,2-diamine (50 mg, 0.42 mmol) and dioxane(10 ml) was stirred at 110° C. for 12 h. The mixture was added water (30mL), extracted with EA (20 mL×3), the extracts were washed with water(25 mL×3) and brine (20 mL×3), dried over Na₂SO₄, concentrated andpurified by flash chromatography (silica gel, 40 g, UV254, PE\EA=100\1to 2\1) to give the title compound (380 mg, 37%) as a gray solid. LC-MS:[M+H]⁺=244.9.

Intermediate B14: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B14.1. LC-MS:[M+H]⁺=291.0.

Intermediate B15:3-(2-(methylsulfonyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-5-(2-bromoethoxy)pyridine (B15.1): A mixture of5-bromopyridin-3-ol (500 mg, 2.87 mmol), 1,2-dibromoethane (810 mg, 4.31mmol), K₂CO₃ (792 mg, 5.74 mmol) and DMF (10 mL) was stirred at rt for12 h. The mixture was diluted with 10 mL water, extracted with EA (10mL×3), the organic layers were washed with water (25 mL×3) and brine (20mL×3), dried over Na₂SO₄, concentrated and purified by flashchromatography (silica gel, 40 g, PE/EA=100/1 to 2/1) to give the titlecompound (200 mg, 20%) as a gray solid. LC-MS: [M+H]⁺=279.9.

3-Bromo-5-(2-(methylsulfonyl)ethoxy)pyridine (B15.2): A mixture of B15.1(200 mg, 0.71 mmol), NaOSOCH₃ (126 mg, 1.07 mmol), and DMSO (2 mL) wasstirred at rt overnight. The mixture was added water (10 mL), extractedwith EA (10 mL×3), the extracts were washed with water (25 mL×3) andbrine (20 mL×3), dried over Na₂SO₄, concentrated and purified by flashchromatography (silica gel, 40 g, PE/EA=100/1 to 2/1) to give the titlecompound (150 mg, 61%) as a gray solid. LC-MS: [M+H]⁺=280.0.

Intermediate B15: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B15.2. LC-MS:[M+H]⁺=328.2.

Intermediate B16: 6-(2-oxopiperazin-1-yl)pyridin-3-ylboronic acid

tert-Butyl 4-(5-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate(B16.1): A mixture of 2,5-dibromopyridine (1.0 g, 4.21 mmol),pyrrolidin-2-one (2.54 g, 12.7 mmol), K₂CO₃ (1.16 g, 8.42 mmol), CuI (40mg, 0.21 mmol), N1,N1,N2,N2-tetramethylethane-1,2-diamine (92 mg, 0.63mmol) and dioxane (10 mL) was stirred at 110° C. for 12 h. The mixturewas added water (30 mL), extracted with EA (20 mL×3), the organic layerswere washed with water (25 mL×3) and brine (20 mL×3), dried over Na₂SO₄,concentrated and purified by flash chromatography (silica gel, 40 g,PE/EA=100/1 to 2/1) to give the title compound (750 mg, 50%) as a graysolid. LC-MS: [M+H]⁺=356.1.

tert-Butyl3-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(B16.2): The title compound was prepared by a method similar to that ofIntermediate B1 by replacing B1.4 with B16.1. The crude product was usedin the next step without further purification. LC-MS: [M+H]⁺=404.0.

Intermediate B16: A mixture of B16.2 (100 mg, 0.31 mmol) in HCl/dioxane(0.6 mL) was stirred at rt for 2 h. The mixture was added water (30 mL),extracted with EA (20 mL×3), the extracts were washed with water (25mL×3) and brine (20 mL×3), dried over Na₂SO₄, concentrated and purifiedby Prep-HPLC to give the title compound (50 mg, 40%) as a gray solid.LC-MS: [M+H]⁺=222.2.

Intermediate B17:N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

4-Bromo-N-(2-hydroxyethyl)benzenesulfonamide (B17.1): To a solution of4-bromobenzene-1-sulfonyl chloride (2.0 g, 7.9 mmol) in DCM (30 mL) wasadded 2-aminoethanol (4.8 g, 79 mmol) and DIPEA (2.0 g, 15.8 mmol) at 0°C., then the reaction mixture was stirred at rt overnight. Theprecipitate was collected by filtration, washed with EtOH (10 mL×2),dried in vacuum to give the title compound (1.8 g, yield 90%) as a whitesolid. LC-MS: [M+H]⁺=281.9.

Intermediate B17: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B17.1. LC-MS:[M+H]⁺=328.0.

Intermediate B18: 6-(2-methylpyrrolidin-1-yl)pyridin-3-ylboronic acid

5-Bromo-2-(2-methylpyrrolidin-1-yl)pyridine (B18.1): To a solution of5-bromo-2-fluoropyridine (5.71 mmol, 1 g) in H₂O (3 mL) was added2-methylpyrrolidine hydrochloride (8.57 mmol, 0.73 g) and K₂CO₃ (11.43mmol, 1.58 g) and the mixture was stirred at 115° C. for 3 h. Themixture was concentrated and purified by flash chromatography (reversephase, C-18, 10 mmol NH₄HCO₃:CH₃OH=0-80%, UV254&UV214) to give the titlecompound (900 mg, 65%) of as a yellow oil. LC-MS: [M+H]⁺=241.1.

Intermediate B18: To a solution of B18.1 (0.622 mmol, 150 mg),bis(pinacolato)diboron (158 mg, 0.622 mmol) and KOAc (1.24 mmol, 121 mg)in dioxane (6 mL) was added Pd(dppf)Cl₂ (0.062 mmol, 45.5 mg). Thereaction mixture was heated at 90° C. for 2 h under N₂. After cooling tothe rt, the mixture was filtered, and the filtrate was used in the nextstep without further purification. LC-MS: [M+H]⁺=207.2.

Intermediate B19:(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)(pyrrolidin-1-yl)methanone

5-Bromo-4-methylpicolinoyl chloride (B19.1): A mixture of5-bromo-4-methylpicolinic acid (5.6 mmol, 1.2 g) and 10 mL thionylchloride was stirred at 90° C. for 2 h. After cooling to the rt, themixture was concentrated to give the title compound (1 g, 77%) as ayellow solid. LC-MS: [M+H]⁺=236.1.

(5-Bromo-4-methylpyridin-2-yl)(pyrrolidin-1-yl)methanone (B19.2): To asolution of pyrrolidine (3.21 mmol, 228 mg) in 10 mL DCM at 0° C. wasadded DIPEA (6.42 mmol, 829 mg). After stirring at 0° C. for 10 min, tothe mixture was added B19.1 (2.14 mmol, 500 mg) portionwise, stirred at0° C. for 20 min, then allowed to warming to rt, and stirred for another2 h, concentrated and purification by flash chromatography (silica gel,PE:EA=0-40%, UV254&UV280 nm) to give the title compound (560 mg, 97%) asa yellow solid. LC-MS: [M+H]⁺=269.1.

Intermediate B19: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B19.2. LC-MS:[M+H]⁺=317.3.

IntermediateB20:4-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

5-Bromo-N,N,4-trimethylpicolinamide (B20.1): To a solution ofdimethylamine hydrochloride (3.21 mmol, 262 mg) in 10 mL DCM at 0° C.was added DIPEA (6.424 mmol, 829 mg). The mixture was stirred at 0° C.for 10 min, B19.1 (2.141 mmol, 500 mg) was added portionwise. Themixture was stirred at 0° C. for 20 min, then warming to rt for 2 h,concentrated and purification by flash chromatography (silica gel,PE:EA=0-50%, UV254&UV280 nm) to give the title compound (560 mg, 97%) asa yellow solid. LC-MS: [M+H]⁺=243.1.

Intermediate B20: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B20.1. LC-MS:[M+H]⁺=291.2.

Intermediate B21:2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol

1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(B21.1): To a solution of3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(300 mg, 1.35 mmol) in CH₃CN (5 mL) was added Cs₂CO₃ (800 mg, 2.702mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (50 mg, 1.892 mmol).The mixture was stirred at 90° C. over night concentrated and purifiedby flash Chromatography (silica gel, PE:EA=0-15%, UV254 &UV280) to givethe title compound (300 mg, 77%) as a yellow oil. LC-MS: [M+H]⁺=381.7.

Intermediate B21: To a solution of B21.1 (300 mg, 0.79 mmol) in THF (6mL) was added TBAF (412 mg, 1.58 mmol). The mixture was stirred at 30°C. for 3 h, concentrated under reduced pressure to give the titlecompound (100 mg, 48%) as a yellow oil. LC-MS: [M+H]⁺=267.

Intermediate B22:1-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.68 mmol, 150 mg) in CH₃CN (5 mL) was added 1-bromo-2-methoxyethane(0.95 mmol, 130.5 mg). The mixture was stirred at 90° C. for 6 h,concentrated under reduced pressure, purified by flash chromatography(silica gel, PE:EA=0-20%, UV254 & UV280 nm) to give the title compound(100 mg, 52%) as a yellow solid. LC-MS: [M+H]⁺=281.5.

Intermediate B23:3-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-3-methyl-2-(methylthio)pyridine (B23.1): A mixture of5-bromo-2-fluoro-3-methylpyridine (1 g, 5.26 mmol), CH₃SNa (479 mg, 6.84mmol) in DMF (10 mL) was stirred for 3.5 h at 0° C. under N₂. Themixture was diluted with 50 mL water, extracted with ethyl acetate (50mL×3). The combined organic layers were successively washed with 50 mLwater and 50 mL brine, dried over Na₂SO₄, concentrated to give the titlecompound (1.1 g, 95%) as a white solid. LC-MS: [M+H]⁺=218.

5-Bromo-3-methyl-2-(methylsulfonyl)pyridine (B23.2): To a mixture ofB23.1 (1.1 g, 5 mmol) in DCM (11 mL) was added m-CPBA (2.58 g, 15 mmol)at 0° C. The mixture was stirred overnight at rt, then quenched by 2mol/L aq. NaOH solution (50 mL), extracted with ethyl acetate (50 mL×2).The combined organic layers were washed successively with 50 mL H₂O and50 mL brine, dried over Na₂SO₄, concentrated to give the title compound(1.2 g, 96%) as a white solid. LC-MS: [M+H]⁺=249.9.

Intermediate B23: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B23.2. LC-MS:[M+H]⁺=216.1 (the ms⁺ of the corresponding boronic acid).

Intermediate B24: (5-methyl-6-morpholinopyridin-3-yl)boronic acid

4-(5-bromo-3-methylpyridin-2-yl)morpholine (B24.1): A mixture of5-bromo-2-fluoro-3-methylpyridine (2.5 g, 13.2 mmol), morpholine (3.4 g,39.6 mmol), K₂CO₃ (5.5 g, 39.6 mmol) in 40 mL DMSO was heated to 120° C.and stirred for 16 h. The mixture was cooled to rt. 200 mL water wasadded, extracted with ethyl acetate (150 mL×3). The combined organiclayers was washed with 150 mL water and 150 mL brine, dried over Na₂SO₄,concentrated to give the title compound (1.8 g, 53%) as a white solid.LC-MS: [M+H]⁺=257.0.

Intermediate B24: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B24.1. LC-MS:[M+H]⁺=223.3.

Intermediate B25:2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol

2-(5-Bromopyridin-2-yl)propan-2-ol (B25.1): To a mixture of1-(5-bromopyridin-2-yl)ethanone (400 mg, 2 mmol) in 8 mL THF was added 6mL CH₃MgBr (1 mol/L) at −15° C. under N₂ atmosphere. The mixture wasstirred for 5 h at 25° C., quenched with sat. NH₄Cl (30 mL) and stirredfor 1 h, extracted with ethyl actetate (50 mL×2). The combined organiclayers were washed with 50 mL water and 50 mL brine, dried over Na₂SO₄,concentrated. The residue was purified on silica gel (PE/EA=10:1) togive title compound (180 mg, 42%) as a colorless oil. ¹H-NMR (400 MHz,CDCl₃) δ ppm 1.54 (s, 6H), 7.31 (dd, 1H), 7.82 (dd, 1H), 8.58 (d, 1H).

Intermediate B25: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B25.1. LC-MS:[M+H]⁺=264.2.

Intermediate B26:4-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

The title compound was prepared by a method similar to that ofIntermediate B23 by replacing 5-bromo-2-fluoro-3-methylpyridine with5-bromo-2-fluoro-4-methylpyridine. LC-MS: [M+H]⁺=298.1.

Intermediate B27:2-methyl-6-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

The title compound was prepared by a method similar to that ofIntermediate B23 by replacing 5-bromo-2-fluoro-3-methylpyridine with3-bromo-6-fluoro-2-methylpyridine. LC-MS: [M+H]⁺=298.1.

Intermediate B28:4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-2-one

4-(5-Bromopyridin-2-yl)piperazin-2-one (B28.1): A mixture of5-bromo-2-fluoropyridine (1 g, 5.68 mmol), piperazin-2-one (1.7 g, 17mmol), K₂CO₃ (2.35 g, 17 mmol) in 20 mL DMSO was heated at 120° C. andstirred for 16 h. The mixture was cooled to rt, 80 mL water was added,extracted with ethyl acetate (60 mL×3), the combined organic layer waswashed with 100 mL water, and 100 mL brine, dried over Na₂SO₄,concentrated, the residue was purified on silica gel (DCM/MeOH=10:1) togive the title compound (250 mg, 17%) as a white solid. LC-MS:[M+H]⁺=255.9.

Intermediate B28: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B28.1. LC-MS:[M+H]⁺=304.3.

Intermediate B29:4,4,5,5-Tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane

Methyl(m-tolyl)sulfane (B29.1): To a mixture of 3-methylbenzenethiol (2g, 16 mmol) in 20 mL of DMF was added NaH (0.96 g, 24 mmol) at 0° C. Themixture was stirred for 30 min at 25° C. After cooling to 0° C., CH₃I(22.7 g, 160 mmol) was added dropwise. The mixture was stirred for 2 hat rt, diluted with 100 mL water, extracted with ethyl acetate (60mL×3). The combined organic layers were washed with brine (50 mL×1),dried over Na₂SO₄, concentrated. The residue was purified by silica gel(eluted with PE/EA=100:0) to give the title compound (1.3 g, 59%) as acolorless oil. The crude product was used in the next step withoutfurther purification.

(4-Bromo-3-methylphenyl)(methyl)sulfane (B29.2): A mixture of B29.1 (1.3g, 9.4 mmol) in 30 mL of AcOH was cooled to 0° C., Br₂ (1.5 g, 9.42mmol) was added dropwise, and the mixture was stirred for 3 h at 25° C.The mixture was concentrated and purified on silica gel (eluted with PE)to give the title compound (1.7 g, 85%) as a colorless oil. The crudeproduct was used in the next step without further purification.

1-Bromo-2-methyl-4-(methylsulfonyl)benzene (B29.3): To a mixture ofB29.2 (1.7 g, 7.83 mmol) in 20 mL DCM was added m-CPBA (4.04 g, 23.5mmol) at 0° C. The mixture was stirred for 16 h at 25° C., quenched by40 mL water, then extracted with DCM (50 mL×2), the combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, concentrated.The residue was purified on silica gel (eluted with PE/EA=7:3) to givethe title compound (1.3 g, 66%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.50 (s, 3H), 3.05 (s, 3H), 7.62 (dd, 2.3 Hz, 1H), 7.74 (d,1H), 7.80 (d, 1H). LC-MS: [M+H]⁺=249.1.

Intermediate B29: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B29.3. The crude productwas used in the next step without further purification. LC-MS:[M+H]⁺=314.0.

Intermediate B30: (6-(3-(dimethylamino)-3-oxopropyl)pyridin-3-yl)boronicacid

(E)-Ethyl 3-(5-bromopyridin-2-yl)acrylate (B30.1): A mixture of5-bromopicolinaldehyde (0.93 g, 5 mmol), ethyl 2-bromoacetate (1.25 g,7.5 mmol), NaHCO₃ (1.26 g, 15 mmol), PPh₃ (1.83 g, 7 mmol), water (10mL) in 5 mL ethyl acetate was stirred for 16 h at 25° C. under N₂atmosphere. The mixture was diluted with water (30 mL), extracted withethyl acetate (40 mL×2), the combined organic layers was washed withwater (40 mL) and brine (40 mL), dried over Na₂SO₄, concentrated. Theresidue was purified on silica gel (PE/EA=6:1) to give the titlecompound (1.1 g, 85%) as a white solid. LC-MS: [M+H]⁺=256.0.

Ethyl 3-(5-bromopyridin-2-yl)propanoate (B30.2): A mixture of B30.1 (1g, 3.9 mmol), CuCl (406 mg, 4.1 mmol) in 20 mL MeOH was cooled to 0° C.,NaBH₄ (1.18 g, 31.2 mmol) was added in portions, the mixture was stirredfor 5 h at 0° C. under N₂ atmosphere. The mixture was filtered,concentrated to dryness. The residue was purified on silica gel (PE/EA=0to 20%) to give the title compound (600 mg, 60%) as a colorless oil.LC-MS: [M+H]⁺=260.0.

3-(5-Bromopyridin-2-yl)propanoic acid (B30.3): A mixture of ethyl B30.2(600 mg, 2.32 mmol), NaOH (928 mg, 23.2 mmol) in the mixed solution ofTHF (14 mL), water (7 mL) and MeOH (7 mL) was stirred for 2 h at 40° C.The mixture was adjusted to pH=2-3 by 1 N HCl, then concentrated. Theresidue was diluted with water (30 mL), extracted with DCM/MeOH (10/1)(40 mL×4), dried over Na₂SO₄, concentrated to give the title compound(375 mg, 70%) as a white solid. LC-MS: [M+H]⁺=232.0.

3-(5-Bromopyridin-2-yl)-N,N-dimethylpropanamide (B30.4): A mixture ofB30.3 (400 mg, 1.74 mmol), dimethylamine hydrochloride (570 mg, 6.96mmol), HATU (992 mg, 2.61 mmol), DIEA (1.79 g, 13.92 mmol) and DCM (20mL) was stirred for 5 h at 25° C. under N₂ atmosphere. The mixture wasdiluted with water (30 mL), extracted with EA (30 mL×3), the combinedorganics was washed with water (40 mL) and brine (40 mL), dried overNa₂SO₄,concentrated. The residue was purified by Prep-HPLC to give thetitle compound (260 mg, 58%) as a white solid. LC-MS: [M+H]⁺=259.0.

Intermediate B30: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B30.4. The crudeproduct was used in the next step without further purification. LC-MS:[M+H]⁺=305.3 for boronic acid pinacol ester; 223.1 for boronic acid.

Intermediate B31:2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine

4-(5-Bromopyridin-2-yl)-2,6-dimethylmorpholine (B31.1):5-bromo-2-fluoropyridine (3.0 g, 20 mmol) was added to a solution of2,6-dimethylmorpholine (6.9 g, 60 mmol) and K₂CO₃ (8.3 g, 60 mmol) in 10mL DMSO. The reaction mixture was heated at 130° C. for 16 h. Thereaction mixture was cooled to rt and 100 mL H₂O was added, followed byextraction with EtOAc (2×100 mL). The organic layers were washedsequentially with brine (100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to give the title compound (4.38 g, 81%) as ayellow solid. LC-MS: [M+H]⁺=273.0.

Intermediate B31: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B31.1. LC-MS:[M+H]⁺=319.0.

Intermediate B32:4,4,5,5-tetramethyl-2-(4-(2-(methylsulfonyl)ethoxy)phenyl)-1,3,2-dioxaborolane

1-Bromo-4-(2-bromoethoxy)benzene (B32.1): A mixture of 4-bromophenol(4.3 g, 25 mmol), 4-bromophenol (12.7 g, 67.5 mmol), NaOH (1.6 g, 40mmol) in H₂O (20 mL) was heated to reflux for 11 h. DCM (50 mL) wasadded. The organic phase was separated and concentrated to give thetitle compound (4.2 g, 60%). The crude product was used in the next stepwithout further purification.

(2-(4-Bromophenoxy)ethyl)(methyl)sulfane (B32.2): A mixture of B32.1(4.3 g, 25 mmol), CH₃SNa (6.12 g, 45 mmol) in DMF (50 mL) was heated at90° C. for 18 h. DCM (50 mL) and water (100 mL) was added. The organicphase was separated and concentrated to give the title compound (2.9 g,80%). The crude product was used in the next step without furtherpurification.

1-Bromo-4-(2-(methylsulfonyl)ethoxy)benzene (B32.3): A mixture of B32.2(2.9 g, 12 mmol), m-CPBA (7.28 g, 36 mmol) in DCM (50 mL) was stirred atrt for 18 h. DCM (50 mL) and water (100 mL) was added. The organic phasewas separated and concentrated. The residue was purified with silica gelchromatography eluted with PE/EtOAc=1/1 to give the title compound (2.7g, 80%) as a pale yellow solid. The crude product was used in the nextstep without further purification.

Intermediate B32: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B32.3. LC-MS:[M+H]⁺=327.2.

Intermediate B33:2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-vinylpyridine (B33.1): Pd(PPh₃)₄ (500 mg, 0.4 mmol) was addedto a stirred suspension of 2,5-dibromopyridine (5 g, 21 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.6 g, 23 mmol) in amixture of 1,4-dioxane (40 mL) and a saturated solution of sodiumcarbonate (12 mL). The mixture was stirred at 100° C. for 16 h in asealed tube under nitrogen. The mixture was diluted with dichloromethane(200 mL) and washed with water (100 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatography(silica gel column, dichloromethane in heptane 20/80 to 80/20) to givethe title compound (2.9 g, 77%). The crude product was used in the nextstep without further purification. LC-MS: [M+H]⁺=186.0.

5-Bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridine (B33.2): B33.1(500 mg, 2.72 mmol) was added to a solution of 3,3-difluoropyrrolidine(930 mg, 8.16 mmol) in acetic acid (3 mL), and the mixture was stirredat 100° C. for 18 h. A saturated aqueous sodium bicarbonate solution wasadded, and the mixture was extracted with ethyl acetate (50 mL). Theorganic layer was dried over anhydrous sodium sulfate, concentrated, andthe residue was then purified by column chromatography on silica gel(hexane:ethyl acetate=10: 1, chloroform:methanol=10: 1) to give thetitle compound (500 mg, 68%). The crude product was used in the nextstep without further purification. LC-MS: [M+H]⁺=293.0.

Intermediate B33: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B33.2. LC-MS: [MH]⁺=257.2(boronic acid's MH⁺).

Intermediate B34: (6-(2-(dimethylamino)ethyl)pyridin-3-yl)boronic acid

2-(5-Bromopyridin-2-yl)-N,N-dimethylethanamine (B34.1): A solution of2.0 M dimethylamine (27 mL, 54 mmol) in THF was added to a solution of5-bromo-2-vinylpyridine (1.0 g, 5.4 mmol) in acetic acid (7 mL). Themixture was stirred at 80° C. overnight and at 90° C. for two days, thenquenched by saturated aqueous sodium bicarbonate solution, extractedwith ethyl acetate, dried over anhydrous sodium sulfate. concentrated,and the residue was then purified by column chromatography on silica gel(hexane:ethyl acetate=10: 1, chloroform:methanol=10: 1) to give thetitle compound (900 mg, 60%). The crude product was used in the nextstep without further purification. LC-MS: [M+H]⁺=231.1.

Intermediate B34: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B34.1. LC-MS:[M+H]⁺=195.2.

Intermediate B35:2-(methoxymethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Methyl 5-bromo-3-methylpicolinate (B35.1): To a solution of5-bromo-3-methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) wasadded SOCl₂ (275 mg, 23.1 mmol) at rt. Then the reaction mixture wasstirred at 90° C. for 4 h. The solvent was removed to give the titlecompound (500 mg, 94%) as a off white solid. The crude product was usedin the next step without further purification. LC-MS: [M+H]⁺=232.0.

(5-Bromo-3-methylpyridin-2-yl)methanol (B35.2): To a solution of B35.1(500 mg, 2.17 mmol) in MeOH (15 mL) was added NaBH₄ (826 mg, 21.7 mmol)at rt. Then the reaction mixture was stirred at 90° C. for 2 h. Thesolvent was removed. The residue was dissolved in EtOAc (20 mL) andwashed with water (15 mL). The organic phase was concentrated to givethe title compound (300 mg, 68%) as a pale yellow oil. The crude productwas used in the next step without further purification. LC-MS:[M+H]⁺=204.2.

5-Bromo-2-(methoxymethyl)-3-methylpyridine (B35.3): Methyl iodide (254mg, 1.79 mmol) was added to a stirred suspension of B35.2 (300 mg, 1.49mmol) and NaH (89 mg, 2.23 mmol) in THF (8 mL). The reaction mixture wasstirred at rt for 1 h. DCM (20 mL) and water (15 mL) were added. Theorganic phase was separated and concentrated. The residue was purifiedwith Prep-TLC (PE/EtOAc=2/1) to give the title compound (310 mg, 96%) asa solid. The crude product was used in the next step without furtherpurification. LC-MS: [M+H]⁺=218.1.

Intermediate B35: The title compound was prepared by a method similar tothat of Intermediate B1 by replacing B1.4 with B35.3. LC-MS:[M+H]⁺=264.0.

Intermediate B36:4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)piperazin-2-one

The title compound was prepared by a method similar to that ofIntermediate B33 by replacing 3,3-difluoropyrrolidine withpiperazin-2-one. LC-MS: [M+H]⁺=332.0.

Intermediate B37:4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1,4-diazepane-1-carbaldehyde

The title compound was prepared by a method similar to that ofIntermediate B31 by replacing 2,6-dimethylmorpholine with1-formyl-1,4-diazepan-6-ylium. LC-MS: [M+H]⁺=332.3.

Intermediate B38:4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)piperazine-1-carbaldehyde

The title compound was prepared by a method similar to that ofIntermediate B33 by replacing 3,3-difluoropyrrolidine withpiperazine-1-carbaldehyde. LC-MS: [M+H]+=346.3.

Intermediate B39:2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethanol

The title compound was prepared by a method similar to that ofIntermediate B31 by replacing 2,6-dimethylmorpholine with2-(piperazin-1-yl)ethanol. LC-MS: [M+H]+=334.2.

Intermediate B40: (6-(Dimethylcarbamoyl)pyridin-3-yl)boronic acid

5-Bromo-N,N-dimethylpicolinamide (B40.1): To a solution of5-bromopicolinic acid (1.5 g, 7.42 mmol) in DCM (15 mL) was added Oxalylchloride (5 mL) at 0° C. The mixture reaction was stirred at 40° C. for1 hr, concentrated under reduced pressure. The residue was diluted withDCM (20 ml), and DIPEA (1.5 g) and dimethylamine (600 mg) was addedsuccessively. The mixture was stirred for 1 h, concentrated, the residuewas purified by flash chromatography by using PE/EA 5:1 to afford thetitle compound (700 mg, 49%). The crude product was used in the nextstep without further purification. LC-MS: [M+H]⁺=231.1.

Intermediate B40: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B40.1. The crudeproduct was used in the next step without further purification. LC-MS:[M+H]⁺=195.4.

Intermediate B41:Pyrrolidin-1-yl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methanone

(5-Bromopyridin-2-yl)(pyrrolidin-1-yl)methanone (B41.1): The titlecompound was prepared by a method similar to that of Intermediate B40.1by replacing dimethylamine with pyrrolidine.

Intermediate B41: To a solution of B41.1 (70 mg), bis(pinacolato)diboron(77 mg, 0.305 mmol) and KOAc (59 mg, 0.604 mmol) in dioxane (2 mL) wasadded Pd(dppf)Cl₂ (20 mg). The reaction mixture was heated at 110° C.for 2 hr under N₂. After cooling to rt, the mixture was filtered, thefiltrate was used in the next step without further purification. LC-MS:[M+H]⁺=303.2 (for boronic acid, LC-MS: [M+H]⁺=221.2.)

Intermediate B42:N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

The title compound was prepared by a method similar to that ofIntermediate B41 by replacing dimethylamine with methanamine. The crudeproduct was used in the next step without further purification. LC-MS:[M+H]⁺=181.1.

Intermediate B43:N-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

The title compound was prepared by a method similar to that ofIntermediate B41 by replacing dimethylamine with ethanamine. The crudeproduct was used in the next step without further purification.

Intermediate B44:N-(2-(Dimethylamino)ethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

The title compound was prepared by a method similar to that ofIntermediate B41 by replacing dimethylamine withN1,N1,N2-trimethylethane-1,2-diamine. The crude product was used in thenext step without further purification. LC-MS: [M+H]⁺=252.2.

Intermediate B45:(5-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)boronic acid

2-(5-Bromopyridin-3-yl)-4,4-dimethyl-4,5-dihydrooxazole (B45.1): Zincchloride (73.7 mg, 0.55 mmol) was placed in a 100 mL round bottom flask,melted three times under high pressure and allowed to cool to ambienttemperature under N₂ before a solution of 5-bromonicotinonitrile (1 g,5.5 mmol) and 2-amino-2-methylpropan-1-ol (513 mg, 5.8 mmol) in drychlorobenzene (15 mL) was added. The resulting mixture was refluxed for48 h under N₂. The volatiles were removed in vacuo and water (20 mL) wasadded. The aqueous layer was extracted with DCM (3×10 mL) and thecombined organic extract was washed with water, brine, dried over Na₂SO₄and concentrated in vacuo. The crude product was purified by flashchromatography on silica gel (PE\EA: 100\1 to 3\1) afforded the titlecompound (1 g, 71%) as a white solid. LC-MS: [M+H]⁺=257.1.

Intermediate B45: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B45.1. LC-MS:[M+H]⁺=221.2.

Intermediate B46:(6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)boronic acid

5-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)picolinamide (B46.1): Thionylchloride (10 mL, 150 mmol) was added to solid 5-bromopicolinic acid (1.2g, 6 mmol) at ambient temperature under N₂. The resulting mixture wasrefluxed for 2 h and the volatiles were removed in vacuo. The crude acidchloride was dissolved in dry DCM (20 mL) and the solution was slowlyadded at 0° C. to a solution of 2-amino-2-methylpropan-1-ol (1.6 g, 18mmol) in DCM (5 mL). After stirring 48 h at ambient temperature,solvents were removed in vacuo and the crude product was purified byflash chromatography on silica gel (PE/EA=100/1 to 5/1) to the titlecompound (1.5 g, 93%) as a white solid. LC-MS: [M+H]⁺=273.1.

2-(5-Bromopyridin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (B46.2): Asolution of B46.1 (1 g, 3.7 mmol) in thionyl chloride (967 mmol, 5 mL)was stirred 12 h at ambient temperature. The solvent was removed invacuo and dry DCM (20 mL) was added. The separated organic layer waswashed with aqueous 2N NaOH (2×25 mL), dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (PE/EA=100/1 to 1/1) to afford the titlecompound (850 mg, 91%) as a white solid. LC-MS: [M+H]⁺=257.0.

Intermediate B46: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B46.2). LC-MS:[M+H]⁺=221.1.

Intermediate B47: (5-(Methoxymethyl)-6-methylpyridin-3-yl)boronic acid

(5-Bromo-2-methylpyridin-3-yl)methanol (B47.1): To a solution of ethyl5-bromo-2-methylnicotinate (1.0 g, 4.1 mmoL) in MeOH (15 mL) was addedsodium borohydride (500 mg, 12.5 mmol) portion wise at 0° C. After 1 h,the reaction was quenched by the addition of water (10 mL). The reactionwas then extracted with DCM (3×10 mL). The extracts were combined, driedover Na₂SO₄, concentrated and purified by column chromatography onsilica gel (PE/EA=100/1 to 5/1) to afford the title compound (650 mg,79%) as a white solid. LC-MS: [M+H]⁺=201.9.

5-Bromo-3-(methoxymethyl)-2-methylpyridine (B47.2): To a mixture ofB47.1 (200 mg, 1.0 mmol) in THF (10 ml) was added NaH (60% wt, 48 mg,1.2 mmol) slowly at 0° C. The mixture was stirred at 0° C. for 30 min,then CH₃I (213 mg, 1.5 mmol) was added dropwise. The reaction mixturewas stirred at 0° C. for another 2 h, quenched by water (5 ml),extracted with EA (10 ml×3), the combined extracts were washed withbrine (10 ml×3), dried over Na₂SO₄, concentrated and purified byPrep-TLC (silica gel, UV254, PE/EA=5/1) to give the title compound (100mg, 70%) as a clear oil. LC-MS: [M+H]⁺=217.9.

Intermediate B47: The title compound was prepared by a method similar tothat of Intermediate B18 by replacing B18.1 with B47.2. LC-MS:[M+H]⁺=182.2.

Intermediate C1:8-bromo-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

(5-Fluorobenzofuran-4-yl)methanamine (C1.1): To a solution of5-fluorobenzofuran-4-carbonitrile (A1.3)(1 g, 6.2 mmol) in MeOH (15 mL)and NH₄OH (2 mL) was added Raney Ni (500 mg) under N₂. The resultingsuspension was degassed under vacuum and backfilled with H₂ via aballoon. The reaction was then stirred at RT under a balloon of H₂overnight, filtered through with a pad Celite. The filtrate wasconcentrated was purified by flash chromatography (DCM-DCM\MeOH=10\1) togive the title compound (900 mg, 88%) as a yellow oil. LC-MS:[M+H]⁺=166.

8-Bromo-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(C1): A mixture of (5-fluorobenzofuran-4-yl)methanamine (C1.1) (203 mg,1.23 mmol) and 8-bromo-5-(methylthio)-[1,2,4]triazolo[4,3-c]pyrimidine(3) (200 mg, 0.82 mmol) was stirred at 40° C. for 12 h. After thecompletion of the reaction, EA (15 mL) was added. The solid was filteredand washed with EA (3 mL×3). The solid was collected to afford the titlecompound as a white solid (50 mg, 17%). LC-MS: [M+H]⁺=362.

Intermediate C2:(4-((8-bromo-[1,2,4]triazolo[4,3-f]pyrimidin-5-ylamino)methyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol

2-Bromo-3,6-difluorobenzaldehyde (C2.1): To a solution of2-bromo-1,4-difluorobenzene (16 g, 83 mol) in 200 mL THF under N₂atmosphere at −78° C. was added LDA (54 mL, 108 mmol) dropwise. Afterstirring at −78° C. for 45 min, DMF (18.2 g, 249 mmol) was added. Themixture was stirred for another 2 h at −78° C. The reaction mixture waswarmed up to 0° C., added 200 mL and sat. NH₄Cl was added. The resultingmixture was extracted with EtOAc (200 mL×2). The combined organic layerwas washed with brine (400 mL×1), dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum to give crude product. The crude productwas purified by column chromatography (silica, EtOAc/PE=1/30) to givethe title compound (11 g, 60%) as a yellow solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.57-7.34 (m, 2H), 10.20 (dd, 1H).

2-Bromo-3-fluoro-6-methoxybenzaldehyde (C2.2): To a solution of2-bromo-3,6-difluorobenzaldehyde (C2.1)(8.4 g, 38.0 mmol) in dry THF (40mL) and MeOH (80 mL) was added a solution of MeONa (2.26 g, 41.8 mmol)in MeOH (40 mL) at 60° C. in a period of 30 min, and the resultingmixture was stirred at 60° C. for 16 h. Solvent was removed and water(100 mL) was added, and the resulting mixture was stirred at RT for 30min. The solid was collected by filtration, and then triturated withPE/EA 10:1 to obtain the title compound as a yellow solid (7.04 g, 80%).¹H NMR (500 MHz, CDCl₃) δ ppm 3.92 (s, 3H), 6.94 (dd, 1H), 7.31-7.24 (m,1H), 10.38 (s, 1H). LC-MS: [M+H]⁺=233.1.

2-Bromo-3-fluoro-6-hydroxybenzaldehyde (C2.3): To a solution of2-bromo-3-fluoro-6-methoxybenzaldehyde (C2.2) (5 g, 21.4 mol) in 100 mLDCM under N₂ at −78° C. was added BBr₃ (26 mL, 26 mmol, 1.0 mol/L inDCM) dropwise. The solution was stirred at −78° C. for 30 min and at rtovernight. 100 mL sat. NH₄Cl was added at 0° C. and stirred for 20 min.The resulting mixture was extracted with DCM (150 mL×2). The combinedorganic layer was washed with 400 mL brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting crude product was purified bycolumn chromatography (gradient elution with 0-50% EA in PE) to give thetitle compound (4 g, 85%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δppm 6.94 (dd, 1H), 7.29 (dt, 1H), 10.33 (s, 1H), 11.78 (s, 1H).

5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (C2.5): Asolution of 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C2.4) (2.7 g, 11.6mol), Zn (CN)₂ (2 g, 17.4 mmol) and Pd(PPh₃)₄ (1.4 g, 1.2 mmol) in 50 mLDMF was stirred under N₂ at 120° C. for 16 h. The reaction mixture wascooled to rt and 150 mL of water was added. The mixture was extractedwith EtOAc (200 mL×2). The combined organic layer was washed with 200 mLbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The resultingcrude product was purified by column chromatography (gradient elution:0-50% EA in PE) to give the title compound (1 g, 60%) as a white solid.¹H NMR (500 MHz, CDCl₃) δ ppm 2.91 (d, 1H), 4.55 (dd, 1H), 4.69 (dd,1H), 5.63 (s, 1H), 7.17-7.01 (m, 2H).

4-(Aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2.6): To asolution of 5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile(C2.5) (1 g, 5.6 mol) in 20 mL THF was added BH₃-THF (22.4 mL, 22.4mmol) dropwise. The solution was stirred at 60° C. for 16 h. Thereaction mixture was cooled to rt, and MeOH was added carefully. Theresulting mixture was stirred for 30 min. The process was repeated forthree times. The crude product was purified by prep-HPLC to give thetitle compound (600 mg, 60%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 3.71 (d, 1H), 3.89 (d, 1H), 4.28 (dd, 1H), 4.52 (dd, 1H), 5.47(dd, 1H)), 6.70 (dd, 1H), 7.00 (dd, 1H).

4-(((8-Bromo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)amino)methyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol(C2): To a solution of4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (3) (400 mg, 1.6mmol) in 2 mL dichloromethane was added4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2.6) (586 mg, 3.2mmol) and the resulting suspension was stirred at 100° C. for 3 h. Themixture was purified by column chromatography (eluted with 10% MeOH inDCM) to give the title compound (105 mg, 17%) as a white solid. LC-MS:[M+H]⁺=382.0.

Intermediate C3:8-bromo-N-((5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

2-Bromo-1-fluoro-4-methoxy-3-(2-methoxyvinyl)benzene (C3.1): To asuspension of (methoxymethyl)triphenylphosphonium (57.41 g, 0.167 mol)in dry THF (250 mL) was added LHMDS (1 M in THF, 178.5 mL, 178.5 mmol)at 0° C. over a period of 30 min. The resulting mixture was stirred at0° C. for 45 min, followed by addition of a solution of2-bromo-3-fluoro-6-methoxybenzaldehyde (C2.2) (26.0 g, 0.11 mol) in dryTHF (100 mL) over in 30 min. The resulting mixture was stirred at 25° C.for 2.5 h, and quenched with NH₄Cl (200 mL), and extracted with Et₂O(150 mL×2). The combined organic layer was washed with brine (150 mL×1),dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by column chromatography (silica, eluent: EtOAc in PE: 3%) toafford the title compound as a yellow solid (25.68 g, 88.2%). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.53 (d, 1H), 6.92-6.82 (m, 1H), 6.77 (dd, 1H),5.99 (d, 1H), 3.84 (s, 3H), 3.75 (s, 3H).

2-(2-Bromo-3-fluoro-6-methoxyphenyl)acetaldehyde (C3.2): To a solutionof 2-bromo-1-fluoro-4-methoxy-3-(2-methoxyvinyl)benzene (C3.1) (25.68 g,98.4 mmol) in THF (200 mL) was added 3 N HCl (100 mL, 300 mmol). Theresulting mixture was heated at 60° C. for 10 h, cooled to rt andextracted with DCM (130 mL×3). The combined organic layer was washedwith NaHCO₃ solution (150 mL×1), brine (150 mL×1), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified with columnchromatography (silica, eluted with EtOAc in PE: 2%-4%). The crudeproduct was triturate with PE/EtOAc (10:1, 30 mL) for 1 h. The solid wascollected by filtration, washed with PE, and dried in vacuo to affordthe title compound as a white solid (13.5 g, 55.5%). ¹H NMR (500 MHz,CDCl₃) δ ppm 3.80 (s, 3H), 3.96 (d, 2H), 6.82 (dd, 1H), 7.07 (dd, 1H),9.67 (t, 1H).

4-Bromo-5-fluoro-2-methoxy-2,3-dihydrobenzofuran (C3.3): To a solutionof 2-(2-bromo-3-fluoro-6-methoxyphenyl)acetaldehyde (C3.2) (11.5 g,46.56 mmol) in DCM (100 mL) at −78° C. was added BBr₃ (1M in DCM, 140mL, 140 mmol) dropwise in 30 min. The resulting mixture was warmed to rtand stirred for 4 h. The mixture was cooled to 0° C., quenched with MeOH(30 mL) carefully and stirred at 0° C. for 2 h. The resulting mixturewas extracted with DCM (100 mL×3), and the combined organic layer waswashed with satd. NaHCO₃ (150 mL×1), brine (150 mL×1), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (silica, eluted with EtOAc in PE 1.0%-4.0%) to afford thetitle compound as a white solid (8.6 g, 75%). ¹H NMR (500 MHz, CDCl₃) δppm 3.06 (dd, 1H), 3.33 (dd, 1H), 3.52 (s, 3H), 5.67 (dd, 1H), 6.70 (dd,1H), 6.90 (t, 1H).

5-Fluoro-2-methoxy-2,3-dihydrobenzofuran-4-carbonitrile (C3.4): Amixture of 4-bromo-5-fluoro-2-methoxy-2,3-dihydrobenzofuran (C3.3) (4.0g, 16.19 mmol), Zn (CN)₂ (3.8 g, 32.39 mmol), Pd(PPh₃)₄ (936 mg, 0.81mmol) in DMF (35 mL) was heated at 120° C. for 16 h. The reactionmixture was extracted with EtOAc (50 mL×4). The combined organic layerswere washed with LiCl (5% aq. 30 mL×2), brine (15 mL×1), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (silica, eluted with EtOAc in PE 2%-4%) to afford thetitle compound as a white solid (2.0 g, 64%). ¹H NMR (500 MHz, CDCl₃) δppm 3.21 (dd, 1H), 3.48 (dd, 1H), 3.53 (s, 3H), 5.73 (dd, 1H), 7.04-6.92(m, 2H).

(5-Fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)methanamine (C3.5): Amixture of 5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-carbonitrile(C3.4) (2.0 g, 8.1 mmol), Raney Ni (0.2 g), in 7 N NH₃ in MeOH (60 mL)and MeOH (30 mL) was purged with H₂ and stirred at rt under H₂ for 30min. The reaction mixture was filtered with Celite and washed with MeOH(100 mL). The filtrate was concentrated in vacuo, and the residue waspurified with column chromatography (silica, eluted with EtOAc in PE10%˜40%; then 1 N NH₃ in MeOH/DCM 10%˜15%) to afford the title compoundas a yellow oil (1.85 g, 90%). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.07 (d,1H), 3.36 (dd, 1H), 3.55-3.48 (m, 3H), 3.81 (d, 2H), 5.65 (dd, 1H), 6.67(dd, 1H), 6.84 (t, 1H). LC-MS: [M+H]⁺=198.2.

8-Bromo-N-((5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(C3): A mixture of(5-fluoro-2-methoxy-2,3-dihydrobenzofuran-4-yl)methanamine (C3.5) (500mg, 2.54 mmol), 8-bromo-5-(methylthio)-[1,2,4]triazolo[4,3-c]pyrimidine(3) (320 mg, 1.30 mmol) in DCM (2 mL) was heating at 50° C. in a openvessel overnight. The reaction mixture was purified by columnchromatography (silica, eluted with EtOAc in PE 10%˜50%; then MeOH inDCM 1%˜3.5%) to afford the title compound as a yellow solid (230 mg,46%). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.20 (d, 1H), 3.44 (dd, 1H), 3.48(s, 3H), 4.79-4.69 (m, 2H), 5.63 (dd, 1H), 6.65 (dd, 1H), 6.79 (t, 1H),6.97 (t, 1H), 7.79 (s, 1H), 9.10 (s, 1H). LC-MS: [M+H]⁺=394.0.

Example 18-(1,3-Dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

To a solution of A1 (70 mg, 0.19 mmol) in dioxane (3 mL) and H₂O (1 mL)was added 1,3-dimethyl-1H-pyrazol-5-ylboronic acid (43.2 mg, 0.31 mmol),NaHCO₃ (49 mg, 0.58 mmol) and Pd(dppf) Cl2 (14.1 mg, 0.019 mmol). Themixture was heated at 95° C. and stirred for 40 min, then concentratedunder reduced pressure. The crude product was purified by prep-HPLC togive the title compound (11 mg, 15%) as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 2.19 (s, 3H), 3.18 (t, 2H), 3.73 (s, 3H), 4.55 (t, 2H),4.72 (s, 2H), 6.29 (s, 1H), 6.72 (dd, 1H), 6.95 (dd, 1H), 7.74 (s, 1H),8.84 (br s, 1H), 9.47 (s, 1H). LC-MS: [M+H]⁺=380.2.

Example 2N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

To a mixture of A1 (40 mg, 0.110 mmol) in 1,4-dioxane (3 mL), MeCN (0.30mL) and water (0.30 mL) was added (2-methylpyridin-3-yl)boronic acid(30.1 mg, 0.220 mmol), potassium carbonate (45.5 mg, 0.330 mmol) andPd(Ph₃P)₄ (12.69 mg, 10.98 μmol). The resulting mixture was stirredunder N₂ at 110° C. for 3 h, cooled to rt, and evaporated under vacuum.The residue was purified on flash chromatography (DCM; MeOH=10:1) toafford Example 2 as a white solid (20 mg, 46.0%).

Alternatively, Example 2 was prepared as follows. To a suspension of A1(25.5 g, 70 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.6g, 140 mmol) and NaHCO₃ (35.3 g, 420 mmol) in a mixture solution of1,4-dioxane (300 mL) and H₂O (100 mL) was added PdCl₂(dppf) (5.94 g, 612mmol). The mixture was degassed with N₂, heated at 110° C. for 1 h. Theresulting mixture was cooled to rt and concentrated under reducedpressure. The residue was purified over column chromatography(EtOAc:MeOH=20:1) to give 14 g of the desired product. 200 mL of acetonewas added to the product, and the resulting suspension was heated at 50°C. for 2 h. The white solid was collected by filtration and dried undervacuum to give Example 2 (13.6 g, 52%)¹H-NMR (500 MHz, DMSO-d₆) δ ppm2.40 (s, 3H), 3.33 (t, 2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H),6.96 (dd, 1H), 7.31 (dd, 1H), 7.66 (s, 1H), 7.74 (d, 1H), 8.51 (d, 1H),8.72 (t, 1H), 9.49 (s, 1H). LC-MS: [M+H]⁺=376.9.

To a suspension of Example 2 (6.0 g, 15.94 mmol) in 100 mL of IPA, asolution of 0.5 N HCl in IPA (33.0 mL, 16.50 mmol) was added dropwise atrt. The suspension was stirred at 50° C. for 12 h, then cooled to rt andstirred for 5 h. The resulting solid was collected by filtration, anddried at 40° C. under vacuum for 2 days to afford the hydrochloride saltof Example 2 as a white solid (6.5 g, 98%) ¹H NMR (DMSO-d₆) δ ppm 2.65(s, 3H), 3.35 (t, 2H), 4.57 (t, 2H), 4.74 (d, 2H), 6.73 (dd, 1H), 6.97(dd, 1H), 7.83 (s, 1H), 7.85-7.94 (m, 1H), 8.46 (d, 1H), 8.80 (dd, 1H),9.07 (t, 1H), 9.58 (s, 1H). LC-MS: [M+H]⁺=376.9.

Example 38-(2,4-Dimethylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid with B1.¹H NMR (500 MHz, DMSO-d₆) δ 2.39 (s, 3H), 2.65 (s, 3H), 3.33 (t, 2H),4.56 (t, 2H), 4.73 (d, 2H), 6.73 (dd, 1H), 6.97 (dd, 1H), 7.72 (s, 1H),8.60 (s, 1H), 8.83 (br s, 1H), 9.50 (s, 1H). LC-MS: [M+H]⁺=392.1.

Example 4N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid with B2.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.43 (d, 6H), 2.35 (s, 3H), 3.30 (t,2H), 4.48-4.56 (m, 3H), 4.69 (d, 2H), 6.70 (dd, 1H), 6.95 (dd, 1H), 7.73(s, 1H), 8.30 (s, 1H), 8.50 (br s, 1H), 9.45 (s, 1H). LC-MS:[M+H]⁺=408.2.

Example 5N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-4-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid with B3.¹H NMR (500 MHz, DMSO-d₆) δ 2.18 (s, 3H), 3.35 (t, 2H), 3.88 (s, 3H),4.56 (t, 2H), 4.71 (d, 2H), 6.73 (dd, 1H), 6.81 (s, 1H), 6.96 (dd, 1H),7.59 (s, 1H), 8.07 (s, 1H), 8.68 (br s, 1H), 9.46 (s, 1H). LC-MS:[M+H]⁺=407.1.

Example 68-(6-Cyclopropyl-2-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid with B4.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-0.97 (m, 4H), 2.09-2.13 (m, 1H),2.31 (s, 3H), 3.30 (t, 2H), 4.55 (t, 2H), 4.71 (s, 2H), 6.71 (dd, 1H),6.96 (dd, 1H), 7.18 (d, 1H), 7.56-7.60 (m, 2H), 8.68 (br s, 1H), 9.46(s, 1H). LC-MS: [M+H]⁺=417.2.

Example 7(3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)methanol

8-(2-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(7.1): The title compound was prepared by using a procedure similar tothat of Example 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acidwith B5. LC-MS: [M+H]⁺=507.1.

Example 7: To a mixture 7.1 (30 mg, 0.08 mmol) in THF (3 mL) was addedTBAF (0.6 mL, 0.6 mmol) and stirred for 4 h. The mixture wasconcentrated and purified by Prep-HPLC to afford the title compound (20mg, 87%) as a white solid. ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 3.34 (t, 2H),4.51 (d, 2H), 4.57 (t, 2H), 4.73 (d, 2H), 5.11 (t, 1H), 6.72 (dd, 1H),6.74 (dd, 1H), 7.44 (dd, 1H), 7.76 (s, 1H), 7.89 (dd, 1H), 8.61 (dd,1H), 8.74 (br s, 1H), 9.48 (s, 1H). LC-MS: [M+H]⁺=393.1.

Example 88-(2-Cyclopropyl-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid with B8.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.08 (m, 4H), 2.21-2.24 (m, 1H),2.36 (s, 3H), 3.33 (t, 2H), 4.56 (t, 2H), 4.72 (d, 2H), 6.72 (dd, 1H),6.96 (dd, 1H), 7.71 (s, 1H), 8.53 (s, 1H), 8.80 (br s, 1H), 9.48 (s,1H). LC-MS: [M+H]⁺=418.1.

Example 9N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-isopropoxy-4-methylpyrimidin-5-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

The title compound was prepared by using a procedure similar to that ofExample 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acid withB10. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (d, 6H), 2.34 (s, 3H), 3.36(t, 2H), 4.57 (t, 2H), 4.72 (s, 2H), 5.28 (t, 1H), 6.72 (dd, 1H), 6.97(dd, 1H), 7.68 (s, 1H), 8.47 (s, 1H), 8.76 (br s, 1H), 9.48 (s, 1H).LC-MS: [M+H]⁺=436.1.

Example 103-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridine1-oxide

N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(10.1): The title compound was prepared by using a procedure similar tothat of Example 1 by replacing 1,3-dimethyl-1H-pyrazol-5-ylboronic acidwith 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. Example10: To a mixture of 10.1 (110 mg, 0.3 mmol) in CHCl₃ (5 mL) was addedmCPBA (163 mg, 0.6 mmol). The reaction mixture was stirred for 16 h atrt. The mixture was concentrated and purified by Prep-HPLC to give thetitle compound (7 mg, 6%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 3.30 (s, 2H), 4.55 (t, 2H), 4.74 (s, 2H), 6.72 (dd, 1H), 6.95 (dd,1H), 7.51 (dd, 1H), 8.12 (d, 1H), 8.19 (d, 1H), 8.32 (d, 1H), 8.98 (s,1H), 9.17 (s, 1H), 9.52 (s, 1H). LC-MS: [M+H]⁺=379.2.

Example 207N-((5-Fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

To a solution of8-bromo-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(C₁) (50 mg, 0.14 mmol) in dioxane (2 ml) was added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45 mg,0.21 mmol), Pd(dppf)Cl₂ (23 mg, 0.028 mmol), NaHCO₃ (35 mg, 0.42 mmol)and water (1 mL). The reaction mixture was purged with N₂ for 3 times,then stirred at 90° C. for 1 h. The mixture was filtered, the solid waswashed with DMSO (2 mL). The filtrate was concentrated and purified byprep-HPLC (NH₄HCO₃) to give the title compound (13 mg, 48%) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 2.40 (s, 3H), 5.01 (s, 2H),7.21-7.25 (m, 2H), 7.31 (dd, 1H), 7.62 (dd, 1H), 7.66 (s, 1H), 7.75 (d,1H), 8.08 (d, 1H), 8.50 (t, 1H), 8.86 (s, 1H), 9.46 (s, 1H). LC-MS:[M+H]⁺=375.1.

Example 233N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

tert-Butyl(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl(8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate(C4.2): A suspension of Pd₂(dba)₃ (18 mg, 0.02 mmol) and Me₄-t-BuXPhos(19.2 mg, 0.04 mmol) in 1.0 mL anhydrous dioxane was heated at 100° C.for 10 min under N₂. The resulting mixture was transferred into astirring suspension of C4.1 (90 mg, 0.2 mmol), 4-methyl-1H-imidazole (72mg, 0.88 mmol) and K₃PO₄ (110 mg, 0.52 mmol) in 2.0 mL anhydrousdioxane. The reaction mixture was stirred at 120° C. overnight, thencooled to rt and filtered, solid residue was washed with EtOAc severaltimes. The filtrate and EtOAc washings were combined and concentratedunder reduced pressure to give the crude product C4.2, which was used inthe next step without purification. LC-MS: [M+H]⁺=466.2.

N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine(233): A solution of C4.2 (93 mg, 0.2 mmol) in 6 mL1,1,1,3,3,3-hexafluoropropan-2-ol was heated in a Biotage MicrowaveReactor at 100° C. for 1 h. Solvent was removed under vacuum to provideyellow oil and was purified by prep-HPLC to give titled compound as awhite solid (19% yield 8 mg). ¹H NMR (500 MHz, DMSO) δ ppm 2.19 (s, 3H),0.31 (t, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 6.71 (dd, 1H), 6.93-6.98 (m,1H), 7.53 (s, 1H), 7.99 (s, 1H), 8.25 (d, 1H), 8.78 (s, 1H), 9.52 (s,1H). LC-MS: [M+H]⁺=366.1.

The following compounds, as identified in Table 2, were prepared usingthe general procedures as well as the procedures from the examplesdescribed above with the appropriate starting materials and reagents.

TABLE 2 ¹H NMR (400 MHz, DMSO-d₆) or Ex # Structure otherwiseindicated/LC-MS Data 11

δ ppm 2.18 (s, 6H), 3.25 (t, 2H), 3.43 (s, 2H), 4.56 (t, 2H), 4.72 (s,2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.38 (d, 2H), 8.01 (s,1H), 8.05 (d, 2H), 8.80 (s, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 401.212

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.12- 3.13 (m, 1H), 3.17 (s, 3H),3.47-3.48 (m, 1H), 4.58 (m, 2H), 4.82 (s, 2H), 6.68 (d, 1H), 6.92 (d,1H), 7.09 (t, 1H), 8.05 (d, 2H), 8.12 (s, 1H), 8.27 (d, 2H), 9.32 (s,1H). LC-MS: [M + H]⁺ = 421.8 13

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.13- 3.14 (m, 1H), 3.47-3.48 (m, 1H),4.58 (t, 2H), 4.79 (s, 2H), 6.68 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H),7.39 (d, 1H), 7.47 (d, 1H), 7.50-7.51 (m, 2H), 7.89-7.91 (m, 3H), 9.32(s, 1H). LC-MS: [M + H]⁺ = 343.9 14

¹H-NMR (400 MHz, CD₃OD) δ ppm 1.57- 1.58 (m, 3H), 1.90-1.92 (m, 4H),2.73- 2.74 (m, 2H), 2.94-2.95 (m, 2H), 3.26- 3.27 (m, 2H), 3.74-3.75 (m,1H), 4.56 (t, 2H), 4.78 (s, 2H), 6.66 (d, 1H), 6.90 (d, 1H), 7.06 (t,1H), 7.51 (d, 2H), 7.93- 7.95 (m, 3H), 9.32 (s, 1H). LC-MS: [M + H]⁺ =440.9 15

¹H NMR (400 MHz, CD₃OD) δ ppm 2.74 (s, 6H), 2.32 (t, 2H), 4.82 (s, 2H),5.49 (s, 2H), 6.68 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 7.89 (d, 2H),8.10 (s, 1H), 8.24 (d, 2H), 9.34 (s, 1H). LC-MS: [M + H]⁺ = 450.8 16

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 6.89 (d,1H), 7.08 (t, 1H), 7.50 (dd, 1H), 8.14 (s, 1H), 8.51 (t, 1H), 8.55 (t,1H), 8.94 (s, 1H), 9.28 (d, 1H), 9.53 (s, 1H). LC-MS: [M + H]⁺ = 345.117

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.48- 3.50 (m, 2H), 4.58 (t, 2H), 4.83 (s,2H), 6.68 (d, 1H), 6.92 (d, 1H), 7.09 (t, 1H), 8.14-8.15 (m, 2H), 8.25(s, 1H), 8.59- 8.61 (m, 2H), 9.34 (s, 1H). LC-MS: [M + H]⁺ = 344.9 18

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.38 (s, 3H), 2.63-2.64 (m, 4H), 3.48-3.49(m, 2H), 3.64-3.65 (m, 4H), 4.57 (t, 2H), 4.81 (s, 2H), 6.68 (d, 1H),6.91 (d, 1H), 7.09 (t, 1H), 7.24 (d, 1H), 7.63 (s, 1H), 8.15-8.17 (m,2H), 9.33 (s, 1H). LC- MS: [M + H]⁺ = 442.9 19

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.01 (s, 3H), 3.47-3.48 (m, 2H), 4.57 (t,2H), 4.79 (s, 2H), 6.68 (d, 1H), 6.91 (d, 1H), 7.09 (t, 1H), 7.37 (d,2H), 7.91-7.92 (m, 3H), 9.31 (s, 1H). LC-MS: [M + H]⁺ = 436.8 20

δ ppm 2.22 (s, 3H), 2.41 (s, 4H), 3.23 (t, 2H), 3.54 (s, 4H), 4.54 (t,2H), 4.69 (s, 2H), 6.68 (d, 1H), 6.87 (d, 1H), 6.93 (d, 1H), 7.05 (d,1H), 7.94 (s, 1H), 8.24 (d, 1H), 8.74 (s, 1H), 8.82 (s, 1H), 9.47 (s,1H). LC-MS: [M + H]⁺ = 442.9 21

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.97 (s, 3H), 4.55-4.60 (m, 2H), 4.79 (s,2H), 5.49 (s, 2H), 6.67 (d, 1H), 6.90-6.94 (m, 2H), 7.09 (t, 1H), 7.90(s, 1H), 8.21- 8.23 (m, 1H), 8.69 (d, 1H), 9.32 (s, 1H). LC-MS: [M + H]⁺= 374.9 22

¹H-NMR (400 MHz, CD₃OD) δ ppm 1.21- 1.28 (m, 3H), 2.30 (s, 6H),2.85-2.91 (m, 1H), 3.41-3.42 (m, 1H), 3.47-3.54 (m, 1H), 4.08 (s, 2H),4.79 (s, 2H), 6.63 (d, 1H), 6.89 (d, 1H), 7.09 (t, 1H), 7.44 (d, 2H),7.89-7.91 (m, 3H), 9.31 (s, 1H). LC-MS: [M + H]⁺ = 414.9 23

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.43 (s, 6H), 3.39-3.41 (m, 2H), 3.72-3.73(m, 2H), 4.60 (t, 2H), 4.85 (s, 2H), 6.67 (dd, 1H), 6.88 (t, 1H), 7.49(d, 2H), 7.95- 7.99 (m, 3H), 9.36 (s, 1H). LC-MS: [M + H]⁺ = 419.1 24

δ ppm 2.06 (s, 3H), 2.15 (s, 3H), 3.25 (t, 2H), 3.72 (s, 3H), 4.55 (t,2H), 4.68 (d, 2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.44 (s,1H), 8.67 (s, 1H), 9.45 (s, 1H). LC-MS: [M + H]⁺ = 376.2 25

δ ppm 3.23 (t, 2H), 3.91 (s, 3H), 4.54 (t, 2H), 4.67 (d, 2H), 6.68 (d,1H), 6.86 (d, 1H), 7.06 (t, 1H), 8.00 (s, 1H), 8.11 (s, 1H), 8.43 (s,1H), 8.66 (t, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 348.1 26

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.22 (s, 3H), 3.28-3.29 (m, 2H), 4.59 (t,2H), 4.83 (s, 2H), 6.70 (d, 1H), 6.94 (d, 1H), 7.10 (t, 1H), 7.86-7.92(m, 2H), 7.99 (s, 1H), 8.13-8.16 (m, 1H), 9.35 (s, 1H). LC-MS: [M + H]⁺= 440.1 27

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.24 (s, 3H), 3.35-3.36 (m, 2H), 4.59 (t,2H), 4.83 (s, 2H), 6.69 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), 7.77 (t,1H), 7.98 (d, 1H), 8.08 (s, 1H), 8.30 (d, 1H), 8.59 (s, 1H), 9.37 (s,1H). LC-MS: [M + H]⁺ = 422.1 28

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.27- 3.29 (m, 5H), 4.59 (t, 2H), 4.84 (s,2H), 6.69 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), 8.19 (d, 1H), 8.23 (s,1H), 8.76 (d, 1H), 9.37 (s, 1H), 9.42 (s, 1H). LC-MS: [M + H]⁺ = 423.129

δ ppm 1.37 (m, 2H), 1.75 (d, 2H), 2.41 (t, 2H), 2.96 (d, 2H), 3.25 (t,2H), 3.33 (t, 2H), 4.55 (t, 2H), 4.74 (s, 2H), 6.70 (d, 1H), 6.89 (d,1H), 7.08 (t, 1H), 7.89 (d, 2H), 8.25 (s, 1H), 8.45 (d, 2H), 9.05 (s,1H), 9.55 (s, 1H). LC-MS: [M + H]⁺ = 491.0 30

δ ppm 2.33 (s, 3H), 3.23 (t, 2H), 3.83 (s, 3H), 4.54 (t, 2H), 4.68 (s,2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, 1H), 7.70 (s, 1H), 8.28 (s,1H), 8.63 (s, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 362.2 31

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.28- 3.29 (m, 2H), 4.59 (t, 2H), 4.81 (s,2H), 6.70 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), 7.25 (t, 1H), 7.29 (d,1H), 7.43-7.49 (m, 1H), 7.76-7.78 (m, 1H), 7.83 (s, 1H), 9.36 (s, 1H).LC-MS: [M + H]⁺ = 362.1 32

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.30 (s, 2H), 4.59 (t, 2H), 4.81 (s, 2H),6.69 (d, 1H), 6.94 (d, 1H), 7.11 (t, 1H), 7.43- 7.46 (m, 2H), 7.54-7.59(m, 2H), 7.70 (s, 1H), 9.32 (s, 1H). LC-MS: [M + H]⁺ = 378.2 33

δ ppm 3.05 (s, 3H), 3.24 (t, 2H), 4.55 (t, 2H), 4.72 (s, 2H), 6.69 (d,1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.46 (t, 1H), 7.97 (dd, 1H), 8.15 (m,2H), 8.92 (s, 1H), 9.39 (s, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 454.934

δ ppm 3.21 (t, 2H), 3.75 (s, 2H), 4.19 (t, 2H), 4.52 (t, 2H), 4.66 (s,2H), 4.93 (s, 1H), 6.68 (d, 1H), 6.86 (d, 1H), 7.05 (t, 1H), 8.00 (s,1H), 8.12 (s, 1H), 8.45 (s, 1H), 8.66 (s, 1H), 9.45 (s, 1H). LC-MS: [M +H]⁺ = 378.2 35

δ ppm 2.19 (s, 6H), 2.47 (t, 2H), 2.74 (t, 2H), 3.24 (t, 2H), 4.55 (t,2H), 4.71 (d, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.31 (d,2H), 7.98 (d, 2H), 8.03 (s, 1H), 8.80 (s, 1H), 9.51 (s, 1H). LC-MS: [M +H]⁺ = 415.0 36

δ ppm 2.24 (s, 3H), 2.31 (s, 3H), 2.50 (t, 4H), 3.12 (t, 4H), 3.24 (t,2H), 4.55 (t, 2H), 4.71 (s, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t,1H), 7.99 (s, 1H), 8.20 (d, 1H), 8.77 (d, 1H), 8.82 (s, 1H), 9.50 (s,1H). LC-MS: [M + H]⁺ = 457.0 37

δ ppm 3.27 (s, 3H), 3.33 (d, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 6.72 (dd,1H), 6.97 (t, 1H), 8.00 (d, 2H), 8.27 (s, 1H), 8.46 (d, 2H), 9.55 (s,1H). LC-MS: [M + H]⁺ = 440.1 38

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 3.25 (m, 2H), 3.74 (m, 2H), 4.04 (m,2H), 4.55 (m, 2H), 4.71 (s, 2H), 4.89 (m, 1H), 6.69 (m, 1H), 6.88 (m,1H), 7.06 (m, 3H), 7.94 (s, 1H), 8.04 (m, 1H), 8.71 (m, 1H), 9.50 (s,1H). LC-MS: [M + H]⁺ = 404.4 39

δ ppm 3.26 (s, 3H), 3.33 (s, 2H), 4.55 (t, 2H), 4.75 (s, 2H), 6.71 (m,1H), 6.96 (t, 1H), 8.00 (d, 2H), 8.27 (s, 1H), 8.46 (d, 2H), 9.52 (s,1H). LC-MS: [M + H]⁺ = 473.2 40

δ ppm 2.79-2.82 (m, 2H), 3.20-3.24 (m, 2H), 3.36-3.40 (m, 2H), 4.51-4.55(m, 2H), 4.67 (s, 2H), 6.64 (d, 1H), 6.90 (d, 1H), 7.02 (t, 1H), 7.78(d, 2H), 8.15 (s, 1H), 8.34 (d, 2H), 9.23 (s, 1H). LC- MS: [M + H]⁺ =467.1 41

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.82- 2.93 (m, 4H), 3.49-3.51 (m, 2H),3.76- 3.77 (m, 2H), 4.59 (t, 2H), 4.81 (s, 2H), 6.69 (d, 1H), 6.93 (d,1H), 7.09 (t, 1H), 7.55 (d, 2H), 8.02 (s, 1H), 8.08 (d, 2H), 9.35 (s,1H). LC-MS: [M + H]⁺ = 456.2 42

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.09 (s, 3H), 3.15 (s, 3H), 4.59 (t, 2H),4.82 (s, 2H), 6.69 (d, 1H), 6.93 (d, 1H), 7.10 (t, 1H), 7.57 (d, 2H),8.03 (s, 1H), 8.07 (d, 2H), 9.35 (s, 1H). LC-MS: [M + H]⁺ = 415.2 43

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.09 (s, 3H), 3.15 (s, 3H), 4.59 (t, 2H),4.82 (s, 2H), 6.69 (d, 1H), 6.93 (d, 1H), 7.10 (t, 1H), 7.57 (d, 2H),8.03 (s, 1H), 8.07 (d, 2H), 9.35 (s, 1H). LC-MS: [M + H]⁺ = 415.2 44

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.41 (t, 2H), 4.60 (t, 2H), 4.85 (s, 2H),6.65- 6.68 (m, 1H), 6.88 (t, 1H), 7.56-7.59 (m, 1H), 8.09 (s, 1H),8.44-8.47 (m, 1H), 8.55 (d, 1H), 9.16 (s, 1H), 9.37 (s, 1H). LC-MS: [M +H]⁺ = 363.1 45

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.41 (t, 2H), 4.60 (t, 2H), 4.87 (s, 2H),6.66- 6.69 (m, 1H), 6.88 (t, 1H), 8.15-8.17 (m, 2H), 8.30 (s, 1H),8.60-8.62 (m, 2H), 9.38 (s, 1H). LC-MS: LC-MS: [M + H]⁺ = 363.1 46

¹H-NMR (400 MHz, MeOH-d₄) δ ppm 1.48 (d, 3H), 1.82-1.85 (m, 4H), 2.46-2.50 (m, 2H), 2.68-2.70 (m, 2H), 3.37- 3.42 (m, 3H), 4.60 (t, 2H), 4.83(s, 2 H), 6.65-6.68 (m, 1H), 6.88 (t, 1H), 7.49 (d, 2H), 7.90 (d, 2H),7.96 (s, 1H), 9.35 (s, 1 H). LC-MS: [M + H]⁺ = 459.2 47

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.36- 3.43 (m, 2H), 4.60 (t, 2H), 4.86 (s,2H), 6.66-6.69 (m, 1H), 6.89 (t, 1H), 7.40- 7.44 (m, 1H), 7.96 (s, 1H),8.60-8.63 (m, 1H), 8.99 (d, 1H), 9.36 (s, 1H). LC- LC-MS: [M + H]⁺ =381.1 48

¹H-NMR (400 MHz, CD₃OD) δ ppm, 3.15-3.28 (m, 2H), 4.54 (t, 2H), 4.69 (d,2H), 6.08 (d, 2H), 6.54 (d, 1H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t,1H), 7.86 (s, 1H), 8.05 (q, 1H), 8.66 (d, 2H), 9.48 (s, 1H). LC-MS: [M +H]⁺ = 360.2 49

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.26 (s, 3H), 2.81 (s, 3H), 3.03 (s, 3H),3.25 (t, 2H), 4.53 (t, 2H), 4.72 (s, 2H), 6.69 (d, 1H), 6.88 (d, 1H),7.06 (t, 1H), 7.23 (d, 1H), 7.97 (m, 3H), 8.86 (s, 1H), 9.51 (s, 1H).LC-MS: [M + H]⁺ = 429.5 50

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.24- 3.30 (m, 2H), 4.56 (t, 2H), 4.72 (d,1H), 6.71 (d, 1H), 6.91 (d, 1H), 7.08 (d, 1H), 7.72 (s, 1H), 7.76 (s,1H), 8.59 (d, 1H), 8.72 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 378.951

δ ppm 3.25 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.71 (d, 1H), 6.90 (d,1H), 7.06 (t, 1H), 8.28 (s, 1H), 9.15 (s, 1H), 9.54 (s, 3H). LC-MS: [M +H]⁺ = 346.5 52

δ ppm 2.49 (s, 4H), 3.24 (t, 2H), 4.54 (t, 2H), 4.71 (s, 2H), 6.69 (d,1H), 6.86 (d, 1H), 7.06 (t, 1H), 7.34 (d, 1H), 8.07 (s, 1H), 8.38 (d,1H), 9.13 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 359.2 53

δ ppm 2.28 (s, 6H), 2.75 (m, 2H), 2.96 (m, 2H), 3.26 (m, 2H), 4.57 (m,2H), 4.72 (m, 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.09 (m, 1H), 7.41 (d,1H), 8.09 (s, 1H), 8.95 (m, 1H), 9.30 (m, 1H), 9.52 (s, 1H). LC- MS:[M + H]⁺ = 416.2 54

δ ppm 3.19-3.25 (t, 2H), 3.97 (s, 3H), 4.52-4.56 (t, 2H), 4.71 (s, 2H),6.68- 6.70 (d, 1H), 6.86-6.88 (d, 1H), 7.05- 7.08 (t, 1H), 8.12 (s, 1H),9.29 (s, 2H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 376.3 55

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.09 (s, 3H), 3.15 (s, 3H), 3.40 (t, 2H),4.60 (t, 2H), 4.83 (s, 2H), 6.65-6.69 (m, 1H), 6.87 (t, 1H), 7.57 (d,2H), 8.06-8.08 (m, 3H), 9.36 (s, 1H). LC-MS: [M + H]⁺ = 433.2 56

¹H-NMR (400 MHz, CD₃OD) δ ppm 3.31 (s, 3H), 3.44 (t, 2H), 4.61 (t, 2H),4.87 (s, 2H), 6.66-6.69 (m, 1H), 6.88 (t, 1H), 8.19 (d, 1H), 8.26 (s,1H), 8.77 (d, 1H), 9.39 (s, 1H), 9.42 (s, 1H). LC-MS: [M + H]⁺ = 441.157

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.61 (s, 3H), 3.41 (t, 2H), 4.60 (t, 2H),4.84 (s, 2H), 6.65-6.68 (m, 1H), 6.88 (t, 1H), 7.44 (d, 1H), 8.04 (s,1H), 8.31 (d, 1H), 9.00 (s, 1H), 9.36 (s, 1H). LC-MS: [M + H]⁺ = 377.2.58

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.72 (d, 2H), 6.71 (q, 2H), 6.87 (d,1H), 7.08 (t, 1H), 7.65 (s, 2H), 8.34 (d, 1H), 8.79 (s, 1H), 9.47 (s,1H). LC-MS [M + H]⁺= 378.5 59

δ ppm 2.20 (s, 3H), 2.38 (s, 3H), 3.25 (t, 2H), 4.56 (t, 2H), 4.70 (s,2H), 6.71 (d, 1H), 6.90 (d, 1H), 7.09 (d, 1H), 7.65 (s, 1H), 8.87 (s,1H), 9.48 (s, 1H). LC-MS [M + H]⁺ = 363.2 60

δ ppm 2.66 (s, 3H), 3.23 (t, 2H), 4.54 (t, 2H), 4.72 (s, 2H), 6.69 (d,1H), 6.87 (d, 1H), 7.06 (t, 1H), 8.20 (s, 1H), 9.01 (s, 1H), 9.39 (s,2H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 360.0 61

δ ppm 3.08 (s, 6H), 3.25 (t, 2H), 4.56 (t, 2H), 4.70 (s, 2H), 6.70 (d,1H), 6.75 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.91 (s, 1H), 8.23 (d,1H), 8.80 (d, 2H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 388.2 62

δ ppm 3.24 (t, 2H), 4.55 (t, 2H), 4.75 (s, 2H), 6.70 (d, 1H), 6.88 (d,1H), 7.07 (t, 1H), 8.13 (d, 1H), 8.39 (s, 1H), 8.86 (q, 1H), 9.08 (d,1H), 9.54 (s, 1H), 9.55 (d, 1H). LC-MS: [M + H]⁺= 370.1 63

δ ppm 1.35 (t, 3H), 3.23 (t, 2H), 4.35 (q, 2H), 4.55 (t, 2H), 4.71 (s,2H), 6.69 (d, 1H), 6.89 (q, 2H), 7.07 (t, 1H), 8.01 (s, 1H), 8.39 (q,1H), 8.56 (d, 2H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 389.0 64

δ ppm 2.36 (s, 3H), 3.27 (t, 2H), 3.81 (s, 3H), 4.56 (t, 2H), 4.69 (d,2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.58 (s, 1H), 7.76 (s,1H), 8.65 (t, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 362.0 65

δ ppm 0.96-1.00 (m, 4H), 2.15 (t, 1H), 3.24 (t, 2H), 4.56 (t, 2H), 4.72(s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.39 (d, 1H), 8.06(s, 1H), 8.36 (q, 1H), 8.87 (s, 1H), 9.07 (s, 1H), 9.51 (s, 1H). LC-MS:[M + H]⁺ = 385.0 66

δ ppm 2.09 (s, 3H), 2.16 (s, 3H), 3.27 (t, 5H), 3.69 (t, 2H), 4.18 (t,2H), 4.58 (t, 2H), 4.69 (d, 2H), 6.71 (d, 1H), 6.91 (d, 1H), 7.09 (t,1H), 7.45 (s, 1H), 8.66 (t, 1H), 9.45 (s, 1H). LC-MS: [M + H]⁺ = 420.767

δ ppm 2.08 (s, 3H), 2.18 (s, 3H), 3.27 (q, 2H), 3.74 (q, 2H), 4.07 (t,2H), 4.57 (t, 2H), 4.69 (s, 2H), 4.91 (t, 1H), 6.71 (d, 1H), 6.91 (d,1H), 7.09 (t, 1H), 7.44 (s, 1H), 9.15 (s, 1H), 9.45 (s, 1H). LC-MS: [M +H]⁺ = 406.6 68

δ ppm 3.25 (t, 2H), 3.57 (d, 4H), 3.68 (s, 4H), 4.55 (t, 2H), 4.74 (s,2H), 6.71 (d, 1H), 6.87 (d, 1H), 7.08 (t, 1H), 7.74 (d, 1H), 8.24 (s,1H), 8.70 (q, 1H), 9.33 (d, 1H), 9.53 (s, 1H). LC-MS [M + H]⁺ = 458.1 69

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.24 (t, 2H), 3.50 (s, 4H), 3.73 (s,4H), 4.55 (t, 2 H), 4.70 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 6.95 (d,1H), 7.07 (dd, 1H), 7.96 (s, 1H), 8.28 (t, 1H), 8.76 (s, 1H), 8.86 (s,1H), 9.50 (s, 1H). LC-MS: [M + H]+ = 430.4 70

δ ppm 2.68 (s, 3H), 3.25 (t, 2H), 3.42 (s, 3H), 4.55 (t, 2H), 4.74 (s,2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.06 (d, 1H), 8.33 (s, 1H), 8.71 (d,1H), 9.02 (s, 1H), 9.27 (d, 1H), 9.55 (s, 1H). LC-MS: [M + H]⁺ = 437.671

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H), 2.37 (s, 3H), 3.33 (d,2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.67 (s,1H), 8.73 (s, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 381.1 72

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.36 (s, 3H), 2.47-2.56 (m, 4H), 3.39 (t,2H), 3.56-3.58 (m, 2H), 3.81-3.83 (m, 2H), 4.60 (t, 2H), 4.85 (s, 2H),6.65-6.68 (m, 1H), 6.88 (t, 1H), 7.56 (d, 2H), 8.06- 8.09 (m, 3H), 7.96(s, 1H), 9.36 (s, 1H). LC-MS: [M + H]⁺ = 488.2 73

δ ppm 2.33 (s, 3H), 3.11 (t, 4H), 3.24 (t, 2H), 3.75 (s, 4H), 4.55 (t,2H), 4.71 (s, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, 1H), 8.00 (s,1H), 8.23 (s, 1H), 8.80 (d, 2H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 444.574

δ ppm 1.17 (d, 6H), 2.44 (t, 2H), 3.24 (t, 2H), 3.64 (t, 2H), 4.21 (d,2H), 4.55 (t, 2H), 4.70 (d, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 6.96 (d,1H), 7.08 (t, 1H), 7.95 (s, 1H), 8.28 (d, 1H), 8.75 (t, 1H), 8.83 (d,1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 458.6 75

δ ppm 3.11 (s, 3H), 3.25 (t, 2H), 3.66 (t, 2H), 4.43 (t, 2H), 4.56 (t,2H), 4.70 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.06- 7.12 (m, 3H), 7.96(s, 1H), 8.08 (d, 2H), 8.76 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ =466.1 76

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 5.82 (s, 2H), 6.62 (d,1H), 6.70 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 7.54 (s, 1H), 8.03 (d,2H), 9.45 (s, 1H). LC-MS: [M + H]⁺ = 360.0 77

δ ppm 2.85 (t, 4H), 3.15 (t, 4H), 3.23 (t, 2H), 4.54 (t, 2H), 4.71 (s,2H), 6.79 (d, 1H), 6.88 (d, 1H), 7.06 (t, 1H), 8.01 (s, 1H), 8.12 (s,1H), 8.24 (s, 1H), 8.66 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 429.078

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.72 (d, 1H), 6.88 (d,1H), 7.08 (t, 1H), 7.23 (d, 1H), 7.59-7.96 (m, 1H), 8.13 (s, 1H), 8.66(dd, 1H), 8.93 (s, 1H), 8.99 (d, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ =411.2 79

¹H -NMR (500 MHz, DMSO-d₆) δ ppm 2.84 (d, 3 H), 3.25 (t, 2H), 4.55 (t, 2H), 4.74 (s, 2 H), 6.71 (d, 1H), 6.90 (d, 1H), 7.08 (t, 1H), 8.11 (d,1H), 8.29 (s, 1H), 8.73 (dd, 1H), 8.81 (dd, 1H), 9.00 (s, 1H), 9.39 (d,1H), 9.54 (s, 1H). ). LC-MS: [M + H]⁺ = 402.3 80

δ ppm 1.88 (d, 4H), 3.25 (t, 2H), 3.53 (t, 2H), 3.70 (t, 2H), 4.55 (t,2H), 4.74 (s, 2H), 6.71 (d, 1H), 6.87 (d, 1H), 7.08 (t, 1H), 7.85 (d,1H), 8.26 (s, 1H), 8.69 (q, 1H), 9.33 (d, 1H), 9.53 (s, 1H). LC-MS: [M +H]⁺ = 442.4 81

¹H-NMR (400 MHz, CD₃OD) δ ppm 2.67- 2.70 (m, 4H), 3.29-3.31 (m, 2H),4.01- 4.04 (m, 4H), 4.59 (t, 2H), 4.79 (s, 2H), 6.69 (d, 1H), 6.93 (t,1H), 7.09 (t, 1H), 7.86 (s, 1H), 8.11 (d, 1H), 8.68 (s, 1H), 9.32 (s,1H). LC-MS: [M + H]⁺ = 446.2 82

¹H-NMR (400 MHz, MeOH-d₄) δ ppm 1.54-1.56 (m, 6H), 2.40 (s, 3H), 3.27-3.28 (m, 4H), 4.49-4.53 (m, 4 H), 4.78 (s, 2 H), 6.69 (d, 1H), 6.92 (d,1H), 7.09 (t, 1H), 7.76 (s, 1H), 8.13 (s, 1H), 9.31 (s, 1 H). LC-MS:[M + H]⁺ = 390.2 83

δ ppm 2.42 (s, 3H), 3.25 (t, 2H), 4.53- 4.58 (m, 4H), 4.73 (d, 2H), 6.70(d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 8.13 (s, 1H), 8.33 (d, 1H), 8.93(t, 1H), 9.05 (d, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 403.3 84

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d, 3H), 3.25 (t, 2H), 4.55 (t,2H), 4.73 (s, 2H), 4.75-4.84 (m, 1H), 5.43 (d, 1H), 6.70 (d, 1H), 6.89(d, 1H), 7.08 (t, 1H), 7.60 (d, 1H), 8.10 (s, 1H), 8.48 (dd, 1H), 8.93(s, 1H), 9.15 (d, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 389.2 85

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.71 (d, 1H), 6.90 (d,1H), 7.08 (t, 1H), 7.50 (dd, 1H), 7.88 (d, 1H), 8.63 (dd, 1H), 9.02 (d,2H), 9.51 (s, 1H). LC- MS: [M + H]⁺ = 363.2 86

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.00 (t, 2H), 3.22-3.27 (m, 5H), 3.72(t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.07(t, 1H), 7.39 (d, 1H), 8.09 (s, 1H), 8.39 (dd, 1H), 8.89 (s, 1H), 9.16(d, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 403.3 87

δ ppm 2.14 (t, 3H), 2.55 (t, 2H), 3.25 (t, 2H), 3.95 (t, 2H), 4.56 (t,2H), 4.74 (s, 2H), 6.70 (s, 1H), 6.90 (s, 1H), 7.08 (t, 1H), 8.15 (s,1H), 8.73 (s, 1H), 8.92 (s, 1H), 9.02 (s, 1H), 9.53 (s, 1H). LC-MS: [M +H]⁺ = 428.2. 88

δ ppm 3.15 (s, 6H), 3.31 (s, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 6.06 (s,1H), 6.70 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.97 (s, 1H), 9.03 (s,1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 389.2 89

δ ppm 2.19 (s, 6H), 2.52-2.54 (m, 2H), 2.78 (t, 2 H), 3.25 (t, 2 H),4.55 (t, 2 H), 4.72 (s, 2 H), 6.70 (d, 1 H), 6.90 (d, 1 H), 7.08 (t, 1H), 7.21 (d, 1 H), 7.37 (t, 3 H), 7.90-8.00 (m, 3 H), 8.83 (s, 1 H),9.51 (s, 1 H). LC-MS: [M + H]⁺ = 415.2 90

δ ppm 1.34 (s, 6H), 3.26 (t, 2H), 4.19 (s, 2H), 4.56 (t, 2H), 4.74 (s,2H), 6.71 (d, 1H), 6.89 (d, 1H), 7.08 (t, 1H), 8.28 (s, 1H), 8.82-9.49(m, 4H), 9.54 (s, 1H). LC- MS [M + H]⁺ = 442.2 91

¹H-NMR (400 MHz, MeOH-d₄) δ ppm 2.67-2.70 (m, 4H), 3.37-3.39 (m, 2H),4.01-4.04 (m, 4H), 4.59-4.60 (m, 2H), 4.80-4.82 (m, 2H), 6.65-6.68 (m,1H), 6.88 (t, 1H), 6.94 (d, 1H), 7.90 (s, 1H), 8.10-8.13 (m, 1H), 8.68(d, 1H), 9.34 (s, 1H). LC-MS: [M + H]⁺ = 464.2 92

¹H-NMR (400 MHz, MeOH-d₄) δ ppm 3.40-3.42 (m, 2H), 3.55-3.58 (m, 4H),3.82-3.85 (m, 4H), 4.58-4.62 (m, 2H), 4.80-4.82 (m, 2H), 6.65-6.68 (m,1H), 6.88 (t, 1H), 6.96 (d, 1H), 7.91 (s, 1H), 8.14-8.16 (m, 1H), 8.71(d, 1H), 9.35 (s, 1 H). LC-MS: [M + H]⁺ = 448.2 93

δ ppm 3.30 (t, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 6.73 (dd, 1H), 6.96 (t,1H), 8.14 (d, 1H), 8.43 (s, 1H), 8.85 (dd, 1H), 9.06 (d, 1H), 9.54 (s,1H), 9.56 (d, 1H). LC-MS: [M + H]⁺ = 388.1 94

δ ppm 3.33 (t, 2H), 4.56 (t, 2H), 4.74 (d, 2H), 6.73 (dd, 1H), 6.97 (t,1H), 7.33 (dd, 2H), 7.45 (d, 1H), 7.85 (t, 2H), 8.84 (d, 1H), 9.49 (s,1H). LC-MS: [M + H]⁺ = 380.0 95

δ ppm 3.03 (d, 6H), 3.25 (t, 2H), 4.55 (t, 2H), 4.74 (d, 2H), 6.70 (d,1H), 6.90 (d, 1H), 7.08 (t, 1H), 7.69 (d, 1H), 8.24 (s, 1H), 8.67 (dd,1H), 9.02 (t, 1H), 9.32 (d, 1H), 9.54 (s, 1H). LC-MS: [M + H]⁺ = 416.296

δ ppm 1.36 (d, 3H), 1.95-1.99 (m, 1H), 2.22-2.37 (m, 3H), 3.31 (t, 2H),3.62 (dd, 1H), 3.80 (t, 1H), 4.38 (t, 1H), 4.60 (t, 2H), 4.82 (s, 2H),6.69 (d, 1H), 6.93 (d, 1H), 7.12 (t, 1H), 7.30 (d, 1H), 8.13 (s, 1H),8.57 (d, 1H), 8.88 (s, 1H), 9.37 (s, 1H). LC-MS: [M + H]⁺ = 428.2 97

δ ppm 3.23 (t, 2H), 3.57-3.64 (m, 11H), 4.55 (t, 2H), 4.70 (s, 2H), 6.69(d, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.07 (t, 1H), 7.96 (s, 1H), 8.28(dd, 1H), 8.76 (s, 1H), 8.85 (d, 1H), 9.50 (d, 1H). LC-MS: [M + H]⁺ =487.2 98

δ ppm 2.16-2.23 (m, 2H), 3.03 (s, 3H), 3.23 (t, 2H), 3.30 (s, 2H), 4.24(t, 2H), 4.54 (t, 2H), 4.72 (s, 2H), 6.68 (d, 1H), 6.88 (s, 1H), 7.06(t, 1H), 8.16 (t, 1H), 8.19 (s, 1H), 8.26 (s, 1H), 8.92 (s, 2H), 9.52(s, 1H). LC-MS: [M + H]⁺ = 481.2 99

δ ppm 1.48 (s, 6H), 3.25 (t, 2H), 4.55 (t, 2H), 4.72 (s, 2H), 5.27 (s,1H), 6.69 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 7.73 (d, 1H), 8.09 (s,1H), 8.45 (m, 1H), 8.88 (s, 1H), 9.13 (s, 1H), 9.53 (s, 1H). LC-MS: [M +H]⁺ = 403.1 100

δ ppm 2.18-2.27 (m, 2H), 2.73 (d, 2H), 2.84 (d, 2H), 2.88-3.00 (m, 4H),3.24 (t, 2H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H),7.07 (t, 1H), 7.41 (d, 1H), 8.09 (s, 1H), 8.39 (dd, 1H), 8.95 (s, 1H),9.16 (d, 1H), 9.54 (s, 1H). LC-MS: [M + H]+ = 478.2 101

δ ppm 1.32 (s, 6H), 3.24 (t, 2H), 4.16 (s, 2H), 4.55 (t, 2H), 4.74 (s,2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.07 (t, 1H), 8.05 (d, 1H), 8.29 (s,1H), 8.70 (dd, 1H), 9.41 (d, 1H), 9.53 (s, 1H), 10.23 (s, 1H). LC-MS:[M + H]⁺ = 442.0. 102

δ ppm 2.04 (s, 3H), 2.31 (s, 3H), 2.52 (t, 2H), 3.03 (s, 3H), 3.25 (t,2H), 3.50 (m, 2H), 4.55 (t, 2H), 4.73 (d, 2H), 6.70 (d, 1H), 6.89 (d,1H), 7.08 (t, 1H), 7.66 (dd, 1H), 8.24 (d, 1H), 8.66 (dd, 1H), 9.04 (t,1H), 9.32-9.34 (m, 1H), 9.56 (s, 1H). LC-MS: [M + H]⁺ = 473.0 103

δ ppm 1.87 (dd, 4H), 2.38 (s, 3H), 3.24 (t, 2H), 3.53 (t, 4H), 4.55 (t,2H), 4.69 (s, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.90 (s,1H), 8.03 (d, 1H), 8.65 (d, 1H), 8.72 (s, 1H), 9.48 (s, 1H). LC-MS: [M +H]⁺ = 428.3 104

δ ppm 2.46 (s, 2H), 3.24 (t, 2H), 3.80 (t, 2 H), 4.09 (s, 2H), 4.55 (t,2H), 4.70 (d, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.06- 7.09 (m, 2H), 8.03(s, 1H), 8.19 (s, 1H), 8.38 (d, 1H), 8.82 (d, 1H), 8.90 (d, 1H), 9.50(s, 1H). LC-MS: [M + H]⁺ = 443.1 105

δ ppm 2.34 (s, 3H), 3.24 (t, 4H), 3.35 (t, 2H), 3.74 (s, 2H), 4.55 (t,2H), 4.70 (s, 2H), 6.71 (d, 1H), 6.88 (d, 1H), 7.09 (t, 1H), 7.90 (s,1H), 8.02 (s, 1H), 8.27 (d, 1H), 8.80 (d, 1H), 8.84 (s, 1H), 9.51 (s,1H). LC-MS: [M + H]⁺ = 457.2 106

δ ppm 3.10 (s, 3H), 3.24 (s, 2H), 3.69 (s, 2H), 4.51-4.56 (m, 4H), 4.72(s, 2H), 6.69 (d, 1H), 6.88 (d, 1H), 7.06 (dd, 1H), 8.16-8.23 (m, 2H),8.30 (s, 1H), 8.99 (s, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 466.9 107

δ ppm 2.40-2.48 (m, 4H), 2.74 (t, 2H), 2.96 (t, 2H), 3.25 (t, 2H),3.33-3.37 (m, 4H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 1H), 6.89 (d,1H), 7.08 (t, 1H), 7.41 (d, 1H), 8.00 (s, 1H), 8.09 (s, 1H), 8.40 (dd,1H), 8.91 (Brs, 1H), 9.16 (d, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 485.2108

δ ppm 1.98 (s, 3H), 2.39-2.47 (m, 4H), 2.72 (t, 2H), 2.95 (t, 2H), 3.25(t, 2H), 3.37-3.44 (m, 4H), 4.55 (t, 2H), 4.72 (s, 2H), 6.70 (d, 1H),6.89 (d, 1H), 7.08 (t, 1H), 7.41 (d, 1H), 8.09 (s, 1H), 8.40 (dd, 1H),8.91 (Brs, 1H), 9.16 (d, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 499.2 109

δ ppm 2.63 (t, 2H), 2.77 (t, 2H), 2.94- 3.00 (m, 4H), 3.14 (t, 2H), 3.25(t, 2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.08(t, 1H), 7.41 (d, 1H), 7.74 (s, 1H), 8.10 (s, 1H), 8.41 (dd, 1H), 8.91(Brs, 1H), 9.17 (d, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 471.3 110

δ ppm 2.44 (t, 2H), 2.50 (t, 2H), 3.42 (t, 2H), 3.35 (t, 2H), 3.54-3.57(m, 6H), 4.47 (t, 1H), 4.55 (t, 2H), 4.70 (d, 2H), 6.70 (d, 1H), 6.87(d, 1H), 6.94 (d, 1H), 7.07 (t, 1H), 7.94 (s, 1H), 8.25 (dd, 1H), 8.74(Brs, 1H), 8.82 (d, 1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 473.2 111

δ ppm 2.82 (d, 3H), 3.24 (t, 2H), 4.55 (t, 2H), 4.69 (s, 2H), 6.35 (d,1H), 6.70 (d, 1H), 6.87-6.95 (m, 2H), 7.07 (t, 1H), 7.66 (s, 1H), 8.39(d, 1H), 8.78 (s, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 392.0 112

δ ppm 3.08 (s, 6H), 3.24 (t, 2H), 4.55 (t, 2H), 4.70 (d, 2H), 6.61 (d,1H), 6.70 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.68 (s, 1H), 8.51 (d,1H), 8.81 (s, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 406.2 113

δ ppm 1.79-1.80 (m, 2H), 3.24 (t, 2H), 3.46 (t, 2H), 3.58 (t, 2H),3.68-3.76 (m, 2H), 3.81-3.89 (m, 2H), 4.55 (t, 2H), 4.70 (s, 2H), 6.70(d, 1H), 6.82 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 7.82 (s, 1H), 7.92(d, 1H), 8.04 (s, 1H), 8.21-8.24 (m, 1H), 8.71 (s, 1H), 8.80 (dd, 1H),9.49 (s, 1H). LC-MS: [M + H]⁺ = 471.2 114

δ ppm 1.15 (t, 3H), 3.25 (t, 2H), 3.37 (t, 2H), 4.55 (t, 2H), 4.74 (s,2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.07 (t, 1H), 8.12 (t, 1H), 8.28 (s,1H), 8.75 (dd, 1H), 8.83 (t, 2H), 9.38 (d, 1H), 9.55 (s, 1H). LC-MS:[M + H]⁺ = 416.0 115

δ ppm 3.13 (t, 2H), 4.54 (t, 2H), 4.75 (s, 2H), 6.71 (dd, 1H), 6.96 (t,1H), 7.49 (d, 1H), 7.95 (s, 1H), 8.25 (t, 1H), 8.51 (td, 1H), 8.89 (s,1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 381.0 116

δ ppm 2.51 (t, 3H), 3.29 (t, 2H), 4.54 (t, 2H), 4.74 (s, 2H), 6.70 (dd,1H), 6.95 (t, 1H), 7.99 (d, 1H), 8.10 (s, 1H), 8.33 (s, 1H), 8.47 (d,1H), 8.94 (s, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 376.9 117

δ ppm 3.23 (t, 2H), 4.22 (t, 2H), 4.48 (t, 2H), 4.54 (t, 4H), 4.71 (s,2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.06 (t, 1H), 8.09 (s, 1H), 8.15 (d,1H), 8.54 (dd, 1H), 8.90 (s, 1H), 9.10 (s, 1H), 9.51 (s, 1H); LC-MS:[M + H]⁺ = 430.2 118

δ ppm 2.24 (s, 3H), 3.34 (t, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd,1H), 6.96 (t, 1H), 7.38 (d, 1H), 7.67 (s, 1H), 8.48 (t, 2H), 9.48 (s,1H). LC-MS: [M + H]⁺ = 377.2 119

¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.04 (dt, 2H), 1.09 (dt, 3H), 2.22 (s,4H), 3.41 (t, 2H), 4.60 (t, 2H), 4.84 (d, 3H), 6.67 (dd, 1H), 6.88 (dd,1H), 7.35 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 8.25 (dd, 1H), 8.94 (d,1H), 9.36 (s, 1H). LC-MS: [M + H]⁺ = 403.2 120

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.41 (t, 2H), 3.55-3.59 (m, 4H), 3.83-3.87 (m, 4H), 4.61 (t, 2H), 4.86 (s, 2H), 6.67 (dd, 1H), 6.84-6.91 (m,1H), 7.30 (dd, 1H), 7.62 (d, 1H), 8.17-8.21 (m, 2H), 9.36 (s, 1H).LC-MS: [M + H]⁺ = 448.0 121

δ ppm 3.32 (d, 2H), 4.56 (t, 2H), 4.71 (d, 2H), 6.73 (dd, 1H), 6.92-7.01(m, 1H), 7.24 (d, 1H), 7.45 (td, 1H), 7.49-7.57 (m, 2H), 7.59 (s, 1H),7.65 (dd, 1H), 7.76 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H). LC- MS: [M +H]⁺ = 387.0 122

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.41 (d, 3H), 4.61 (t, 2H), 4.87 (d,2H), 5.52 (s, 1H), 6.68 (dd, 1H), 6.86-6.95 (m, 1H), 7.56-7.65 (m, 2H),7.78-7.88 (m, 2H), 7.90-7.97 (m, 2H), 9.37 (s, 1H). LC-MS: [M + H]⁺ =405.0 123

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.49 (s, 3H), 3.34-3.36 (m, 2H), 4.60(t, 2H), 4.82 (s, 2H), 6.70 (d, 1H), 6.95 (d, 1H), 7.12 (t, 1H), 7.41(s, 1H), 7.70 (s, 1H), 7.85 (dd, 1H), 8.51 (dd, 1H), 9.34 (s, 1H) LC-MS:[M + H]⁺ = 359.0 124

δ ppm 3.32 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (dd, 1H), 6.96 (t,1H), 7.73 (d, 1H), 7.79 (s, 1H), 8.59 (d, 1H), 8.72 (d, 2H), 9.49 (s,1H). LC-MS: [M + H]⁺ = 397.1 125

δ ppm 3.05 (t, 2H), 3.25 (t, 2H), 3.47 (s, 2H), 3.89 (t, 2H), 4.55 (t,2H), 4.72 (s, 2H), 6.69 (d, 1H), 6.89 (d, 1H), 7.07 (t, 1H), 7.95 (d,1H), 8.13 (s, 1H), 8.50 (dd, 1H), 9.08 (s, 1H), 9.17 (s, 1H), 9.53 (s,1H). LC-MS: [M + H]⁺ = 443.2 126

δ ppm 3.24 (t, 2H), 3.71 (q, 2H), 4.20 (t, 2H), 4.53-4.61 (m, 3H), 4.70(d, 2H), 5.69 (d, 1H), 6.50 (d, 1H), 6.69 (d, 1H), 6.86 (d, 1H), 7.07(t, 1H), 7.91 (s, 1H), 8.21 (dd, 1H), 8.74-8.76 (m, 2H), 9.49 (s, 1H).LC-MS: [M + H]⁺ = 416.2 127

δ ppm 2.41 (s, 3H), 3.35 (t, 5H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (dd,1H), 6.96 (t, 1H), 7.79 (s, 1H), 8.08 (s, 1H), 8.72 (d, 2H), 9.51 (s,1H). LC-MS: [M + H]⁺ = 455.1 128

δ ppm 2.33 (s, 3H), 3.28 (s, 3H), 3.35 (t, 2H), 4.57 (t, 2H), 4.73 (t,2H), 6.73 (dd, 1H), 6.98 (t, 1H), 7.63 (d, 1H), 7.68 (s, 1H), 7.82 (dd,1H), 7.91 (s, 1H), 8.79 (s, 1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 454.1129

δ ppm 1.87 (t, 4H), 3.34 (t, 2H), 3.53 (t, 2H), 3.68 (dd, 2H), 4.56 (t,2H), 4.74 (s, 2H), 6.73 (dd, 1H), 6.96 (t, 1H), 7.84 (d, 1H), 8.29 (s,1H), 8.69 (dd, 1H), 8.90 (s, 1H), 9.36 (d, 1H), 9.53 (s, 1H). LC-MS:[M + H]⁺ = 460.2 130

δ ppm 1.83-1.88 (m, 4H), 2.31 (s, 3H), 3.23 (t, 2H), 3.54 (t, 2H), 3.67(t, 2H), 4.57 (t, 2H), 4.74 (d, 2H), 6.73 (dd, 1H), 6.98 (t, 1H), 7.71(s, 1H), 7.73 (s, 1H), 8.52 (s, 1H), 8.81 (s, 1H), 9.49 (s, 1H). LC-MS:[M + H]⁺ = 474.1 131

δ ppm 2.30 (s, 3H), 3.03 (d, 6H), 3.37 (t, 2H), 4.57 (t, 2H), 4.73 (s,2H), 6.74 (dd, 1H), 6.98 (t, 1H), 7.55 (s, 1H), 7.73 (s, 1H), 8.50 (s,1H), 8.81 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 448.2 132

δ ppm 2.07 (s, 3H), 2.15 (s, 3H), 3.32 (t, 2H), 3.72 (s, 3H), 4.58 (t,2H), 4.70 (d, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.47 (s, 1H), 8.54 (t,1H), 9.43 (s, 1H). LC-MS: [M + H]⁺ = 394.2 133

δ ppm 2.64 (t, 2H), 3.02 (s, 2H), 3.18 (s, 2H), 3.25 (t, 2H), 3.72 (s,2H), 4.55 (t, 2H), 4.73 (s, 2H), 6.70 (d, 1H), 6.89 (d, 1H), 7.07 (t,1H), 7.54 (d, 1H), 7.79 (s, 1H), 8.13 (s, 1H), 8.51 (dd, 1H), 8.93 (s,1H), 9.21 (d, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 457.2 134

δ ppm 3.24 (t, 2H), 3.50-3.62 (m, 8H), 4.55 (t, 2H), 4.68 (s, 2H), 6.68(d, 1H), 6.88 (d, 1H), 7.00-7.08 (d, 1H), 7.94 (s, 1H), 8.12 (s, 1H),8.28 (d, 1H), 8.85 (s, 1H), 9.44 (s, 1H). LC-MS: [M + H]⁺ = 457.2 135

δ ppm 2.76-2.82 (m, 5H), 2.98-3.02 (m, 5H), 3.22 (t, 2H), 4.55 (t, 2H),4.72 (s, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.08 (t, 1H), 7.39 (d, 1H),8.08 (s, 1H), 8.37 (dd, 1H), 8.91 (s, 1H), 9.14 (d, 1H), 9.51 (s, 1H).LC-MS: [M + H]⁺= 444.0 136

δ ppm 3.33 (t, 2H), 4.56 (t, 2H), 4.76 (s, 2H), 6.73 (dd, 1H), 6.96 (t,1H), 8.16 (d, 1H), 8.41 (s, 1H), 8.96 (dd, 1H), 9.05 (s, 1H), 9.54 (d,2H). LC-MS: [M + H]⁺ = 431.1 137

δ ppm 2.49 (s, 3H), 3.25 (t, 2H), 3.41 (s, 3H), 4.53 (t, 2H), 4.51 (s,2H), 4.72 (s, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.08 (t, 1H), 8.08 (s,1H), 8.41 (d, 1H), 8.90 (t, 1H), 9.03 (d, 1H), 9.51 (s, 1H). LC-MS: [M +H]⁺ = 403.2 138

δ ppm 3.36 (t, 2H), 3.94 (s, 3H), 4.57 (t, 2H), 4.72 (s, 2H), 6.74 (dd,1H), 6.97 (t, 1H), 7.19 (s, 1H), 7.69 (s, 1H), 8.31 (s, 1H), 8.82 (Brs,1H), 9.48 (s, 1H). LC-MS: [M + H]⁺ = 427.0 139

δ ppm 2.54 (s, 3H), 3.24-3.34 (m, 5H), 4.56 (t, 2H), 4.74 (s, 2H), 6.72(dd, 1H), 6.98 (t, 1H), 7.78 (s, 1H), 7.98 (d, 1H), 8.14 (d, 1H), 8.87(s, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 454.9 140

δ ppm 2.50 (s, 2H), 2.54 (s, 2H), 3.33 (t, 2H), 4.56 (t, 2H), 4.74 (s,2H), 6.73 (dd, 1H), 6.96 (t, 1H), 7.78 (s, 1H), 7.99 (d, 1H), 8.14 (d,1H), 8.87 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 434.1 141

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.38 (t, 2H), 3.92 (s, 3H), 4.56-4.60(m, 2H), 4.82 (s, 2H), 6.62-6.68 (m, 1H), 6.87 (dd, 1H), 7.08 (dd, 1H),7.89 (s, 1H), 8.00 (dd, 1H), 8.18 (dd, 1H), 9.30 (s, 1H). LC-MS: [M +H]⁺ = 393.0 142

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.34-3.40 (m, 2H), 3.95 (s, 3H), 4.58(d, 2H), 4.81 (s, 2H), 6.64 (dd, 1H), 6.85 (t, 1H), 6.91 (d, 1H), 7.92(s, 1H), 8.21 (dd, 1H), 8.68 (d, 1H), 9.32 (s, 1H). LC-MS: [M + H]⁺ =393.0 143

δ ppm 1.34 (t, J = 7.18 Hz, 3H) 3.29-3.38 (m, 2H) 4.17 (q, J = 7.15 Hz,2H) 4.60 (t, J = 8.72 Hz, 2H) 4.76 (s, 2H) 6.40-6.50 (m, 1H), 6.75 (dd,J = 8.63, 3.80 Hz, 1H) 7.00 (t, J = 9.44 Hz, 1H) 7.55-7.62 (m, 1H) 7.72(s, 1 H) 9.44 (s, 1 H). LC-MS: [M + H]⁺ = 379.9 144

δ ppm 1.31-1.39 (m, 6H), 3.39 (m, 2H), 4.40-4.49 (m, 1H), 4.56 (t, J =8.8 Hz, 2H), 4.72 (s, 2H), 6.36 (d, J = 1.8 Hz, 1H), 6.73 (dd, J = 8.7,3.9 Hz, 1H), 6.93-7.01 (m, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.68 (s, 1H),9.48 (s, 1H). LC-MS: [M + H]⁺ = 394.0 145

δ ppm 3.31 (t, 2H), 3.89 (s, 3H), 4.55 (t, 2H), 4.75 (s, 2H), 6.71 (q,1H), 6.96 (t, 1 H), 7.77 (t, 2H), 8.21 (t, 1H), 8.37 (s, 1H), 8.97 (s,1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 393.2 146

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.38 (t, 2H), 4.58 (td, 2H), 4.82 (s,2H), 6.65 (dd, 1H), 6.81-6.89 (m, 1H), 7.45- 7.49 (m, 2H), 7.55 (ddd,2H), 7.61-7.66 (m, 2H), 7.91-7.95 (m, 2H), 7.97 (s, 1H), 9.33 (s, 1H).LC-MS: [M + H]⁺: [M + H]⁺ = 429.9 147

δ ppm 3.25 (t, 2H), 3.88 (s, 3H), 4.54 (t, 2H), 4.67 (s, 2H), 6.70 (d,1H), 6.95 (t, 1H), 8.04 (s, 1H), 8.12 (s, 1H), 8.44 (s, 1H), 8.54 (s,1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 366.1 148

δ ppm 1.50 (d, 6H), 3.30 (t, 2H), 4.55 (t, 2H), 4.71 (s, 3H), 6.72 (dd,1H), 6.97 (t, 1H), 7.67 (s, 1H), 8.50 (s, 1H), 8.73 (s, 1H), 9.48 (s,1H). LC-MS: [M + H]⁺ = 462.0 149

δ ppm 1.00-1.09 (m, 4H), 3.23 (t, 2H), 3.81 (dd, 1H), 4.54 (t, 2H), 4.68(d, 2H), 6.69 (d, 1H), 6.87 (d, 1H), 7.07 (t, 1H), 8.01 (s, 1H), 8.13(s, 1H), 8.48 (s, 1H), 8.67 (s, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ =374.2 150

δ ppm 0.97-1.09 (m, 4H), 3.30 (t, 2H), 3.79-3.83 (m, 1H), 4.54 (t, 2H),4.70 (s, 2H), 6.71 (dd, 1H), 6.95 (t, 1H), 8.05 (s, 1H), 8.14 (s, 1H),8.48 (s, 1H), 8.56 (d, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 392.2 151

δ ppm 1.39 (d, 6H), 2.08 (s, 3H), 2.16 (s, 3H), 3.36 (t, 2H), 4.48-4.58(m, 3H), 4.70 (d, 2H), 6.74 (dd, 1H), 6.99 (t, 1H), 7.49 (s, 1H), 8.54(t, 1H), 9.44 (s, 1H). LC-MS: [M + H]⁺ = 422.2 152

δ ppm 3.25 (t, 2H), 3.83 (s, 3H), 4.56 (t, 2H), 4.72 (d, 2H), 6.51 (d,1H), 6.71 (d, 1H), 6.90 (d, 1H), 7.09 (t, 1H), 7.51 (s, 1H), 7.75 (s,1H), 8.98 (d, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 348.2 153

δ ppm 1.39 (d, 6H), 2.08 (s, 3H), 2.16 (s, 3H), 3.25 (t, 2H), 4.46-4.57(m, 3H), 4.69 (s, 2H), 6.71 (d, 1H), 6.91 (d, 1H), 7.10 (t, 1H), 7.45(s, 1H), 8.66 (s, 1H), 9.45 (s, 1H). LC-MS: [M + H]⁺ = 404.2 154

δ ppm 3.25 (t, 2H), 4.55 (t, 2H), 4.74 (d, 2H), 6.70 (d, 1H), 6.88 (t,1H), 7.02- 7.16 (m, 2H), 7.81 (d, 1H), 8.27 (s, 1H), 8.77 (dd, 1H), 9.05(t, 1H), 9.41 (d, 1H), 9.54 (s, 1H). LC-MS: [M + H]⁺ = 395.1 155

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.35 (s, 3H), 3.36-3.42 (m, 2H), 3.94(s, 4H), 4.57 (d, 2H), 4.81 (s, 2H), 6.62- 6.67 (m, 1H), 6.68-6.74 (m,1H), 6.87 (t, 1H), 7.62 (d, 2H), 9.31 (s, 1H). LC-MS: [M + H]⁺ = 407.0156

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.25 (s, 3H), 3.36-3.41 (m, 2H), 4.58(t, 2H), 4.80 (s, 2H), 6.52 (d, 1H), 6.65 (dd, 1H), 6.83-6.89 (m, 1H),7.43 (d, 1H), 7.60 (s, 1H), 9.29 (s, 1H). LC-MS: [M + H]⁺ = 392.0 157

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.39 (t, 2H), 4.58 (t, 2H), 4.82 (s,2H), 6.65 (dd, 1H), 6.86 (d, 1H), 7.20 (td, 2.9 Hz, 2H), 7.40 (dd, 1H),7.56 (dd, 1H), 7.71 (s, 1H), 7.90-7.96 (m, 1H), 9.31 (s, 1H). LC-MS:[M + H]⁺ = 414.0 158

δ ppm 2.08 (s, 3H), 2.18 (s, 3H), 3.31 (t, 2H), 3.73 (dd, 3H), 4.06 (t,2H), 4.56 (t, 2H), 4.70 (d, 2H), 4.93 (t, 1H), 6.74 (dd, 1H), 6.99 (t,1H), 7.47 (s, 1H), 8.55 (s, 1H), 9.44 (s, 1H). LC-MS: [M + H]⁺ = 424.2159

δ ppm 2.08 (s, 3H), 2.16 (s, 3H), 3.26 (s, 3H), 3.31 (t, 2H), 3.69 (t,2H), 4.18 (t, 2H), 4.58 (t, 2H), 4.70 (d, 1H), 6.74 (dd, 1H), 6.99 (t,1H), 7.48 (s, 1H), 8.55 (t, 1H), 9.43 (s, 1H). LC-MS: [M + H]⁺ = 438.2160

δ ppm 3.33 (t, 2H), 4.57 (t, 2H), 4.77 (s, 2H), 6.72 (dd, 1H), 6.97 (t,1H), 8.02 (d, 1H), 8.38 (s, 1H), 8.89 (d, 1H), 9.02 (s, 1H), 9.50 (s,1H), 9.54 (s, 1H). LC-MS: [M + H]⁺ = 431.2 161

δ ppm 3.30-3.33 (m, 2H), 3.94 (s, 3H), 4.57 (t, 2H), 4.73 (s, 2H), 6.73(dd, 1H), 6.92-6.99 (m, 2H), 7.80 (s, 1H), 8.58 (d, 1H), 8.82 (s, 1H),9.48 (s, 1H). LC-MS: [M + H]⁺ = 411.2 162

δ ppm 3.28 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (m, 1H), 6.97 (t,1H), 7.71 (d, 1H), 7.88 (s, 1H), 8.61 (d, 1H), 8.78 (s, 1H), 8.97 (s,1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 397.1 163

δ ppm 2.25 (s, 3H), 3.34 (d, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd,1H), 6.96 (t, 1H), 7.42 (d, 1H), 7.71 (s, 1H), 8.47 (d, 1H), 8.53 (s,1H), 8.81 (s, 1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 377.1 164

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.42 (d, 3H), 3.44 (t, 2H), 4.62 (t,2H), 4.85 (s, 3H), 6.63-6.74 (m, 1H), 6.90 (t, 1H), 704 (d, 1H), 7.73(d, 1H), 7.94 (t, 1H), 9.36 (d, 1H). LC-MS: [M + H]⁺ = 395.0 165

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.25 (s, 3H), 3.43 (t, 2H), 4.63 (d,2H), 4.84 (s, 2H), 6.69 (dd, 1H), 6.90 (t, 1H), 7.04 (t, 1H), 7.12 (dd,1H), 7.36 (dd, 1H), 7.64 (s, 1H), 9.34 (s, 1H). LC-MS: [M + H]⁺ = 394.0166

¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.42 (t, 2H), 4.62 (td, 2H), 4.87 (d,3H), 6.66-6.72 (m, 1H), 6.91 (t, 1H), 7.70 (s, 1H), 7.79 (dd, 1H), 8.09(d, 1H), 8.80 (d, 1H), 9.36 (d, 1H). LC-MS: [M + H]⁺ = 431.1 167

δ ppm 2.35 (s, 3H), 2.44 (s, 3H), 3.31 (t, 2H), 4.56 (t, 2H), 4.72 (s,2H), 6.73 (dd, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.62 (d, 2H), 8.70 (s,1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 391.1 168

δ ppm 3.37 (t, 2H), 4.57 (t, 2H), 4.73 (s, 2H), 6.72-7.06 (m, 3H), 7.64(s, 1H), 7.71 (dd, 1H), 8.03 (d, 1H), 8.78 (d, 2H), 8.83 (d, 2H), 9.49(s, 1H). LC-MS: [M + H]⁺ = 413.2 169

δ ppm 3.32 (t, 2H), 3.83 (s, 3H), 4.56 (t, 2H), 4.73 (d, 2H), 6.52 (d,1H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.51 (d, 1H), 7.78 (s, 1H), 8.87 (d,1H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 366.2 170

δ ppm 3.30 (t, 2H), 4.02 (s, 3H), 4.55 (t, 2H), 4.71 (d, 2H), 6.72 (d,1H), 6.97 (t, 1H), 7.67 (s, 1H), 8.47 (s, 1H), 8.73 (d, 1H), 9.48 (s,1H). LC-MS: [M + H]⁺ = 434.1 171

δ ppm 1.93 (s, 3H), 3.32 (t, 2H), 4.42 (d, 2H), 4.55 (t, 2H), 4.74 (s,2H), 6.72 (dd, 2H), 6.97 (t, 1H), 7.48 (s, 1H), 8.19 (s, 1H), 8.55 (d,2H), 8.87 (s, 1H), 9.26 (s, 1H), 9.52 (s, 1H). LC-MS: [M + H]⁺ = 434.3172

δ ppm 2.37 (s, 3H), 3.29 (t, 2H), 3.82 (s, 3H), 4.56 (t, 2H), 4.70 (s,2H), 6.71 (dd, 1H), 6.97 (t, 1H), 7.62 (s, 1H), 7.76 (s, 1H), 8.53 (s,1H), 9.45 (s, 1H). LC-MS: [M + H]⁺ = 380.2 173

δ ppm 0.93-1.03 (m, 4H), 2.09-2.13 (m, 1H), 2.19 (s, 3H), 3.33 (t, 2H),4.55 (t, 2H), 4.71 (d, 2H), 6.72 (q, 1H), 6.96 (t, 1H), 7.27 (s, 1H),7.61 (s, 1H), 8.28 (s, 1H), 8.709 (t, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺= 417.3 174

δ ppm 3.31 (t, 2H), 3.98 (s, 3H), 4.55 (t, 2H), 4.74 (s, 2H), 6.71 (q,1H), 6.96 (t, 1H), 8.17 (s, 1H), 8.84 (s, 1H), 9.30 (s, 2H), 9.51 (s,1H). LC-MS: [M + H]⁺ = 394.2 175

δ ppm 2.36 (s, 3H), 3.27 (s, 2H), 3.96 (s, 3H), 4.56 (t, 2H), 4.71 (s,2H), 6.72 (dd, 1H), 6.98 (t, 1H), 7.66 (s, 1H), 8.50 (s, 1H), 8.79 (s,1H), 9.43 (s, 1H). LC-MS: [M + H]⁺ = 408.2 176

δ ppm 2.45 (s, 3H), 3.26 (t, 2H), 4.57 (t, 2H), 4.74 (s, 2H), 6.72 (dd,1H), 6.97 (t, 1H), 7.77 (s, 1H), 8.74 (s, 1H), 9.09 (s, 1H), 9.50 (s,1H). LC-MS: [M + H]⁺ = 378.2 177

δ ppm 2.14 (s, 3H), 2.51 (s, 3H), 3.30 (t, 2H), 4.54 (t, 2H), 4.69 (s,2H), 6.68 (q, 1H), 6.94 (t, 1H), 7.72 (d, 1H), 7.58 (s, 1H), 8.27 (d,1H), 8.81 (s, 1H), 9.31 (s, 1H). LC-MS: [M + H]⁺ = 391.2 178

δ ppm 2.34 (s, 3H), 3.43 (d, 2H), 4.64 (s, 2H), 4.85 (d, 2H), 6.71 (d,1H), 6.93 (d, 1H), 7.58 (d, 1H), 7.70 (d, 1H), 7.74 (s, 1H), 7.77 (s,1H), 9.38 (s, 1H). LC- MS: [M + H]⁺ = 401.0 179

δ ppm 0.97-1.04 (m, 4H), 2.04 (s, 3H), 2.24 (s, 3H), 3.48-3.51 (m, 3H),4.55 (t, 2H), 4.68 (d, 2H), 6.72 (t, 1H), 6.95 (t, 1H), 7.47 (s, 1H),8.54 (t, 1H), 9.42 (s, 1H). LC-MS: [M + H]⁺ = 420.3 180

δ ppm 2.17 (s, 3H), 3.33 (t, 2H), 4.57 (t, 2H), 4.73 (d, 2H), 6.72 (dd,1H), 6.95 (t, 1H), 7.42 (d, 1H), 7.77 (s, 1H), 8.12 (d, 1H), 8.89 (s,1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 395.1 181

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.43 (t, 3H), 3.46 (s, 2H), 4.63 (d,2H), 4.87-4.89 (m, 3H), 6.71 (dd, 1H), 6.83- 7.00 (m, 2H), 7.61 (d, 1H),7.80 (s, 1H), 8.57 (d, 1H), 9.39 (s, 1H). LC-MS: [M + H]⁺ = 427.0 182

¹H NMR (400 MHz, MeOH-d₄) δ ppm 2.36 (d, 3H), 3.46 (t, 2H), 4.64 (t,2H), 4.88 (d, 2H), 5.61 (s, 1H), 5.73 (s, 1H), 6.72 (d, 1H), 6.86-6.97(m, 1H), 7.48- 7.55 (m, 1H), 7.79 (s, 1H), 8.51 (d, 1H), 9.39 (s, 1H).LC-MS: [M + H]⁺ = 409.0 183

δ ppm 2.23 (s, 3H), 3.27 (s, 2H), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd,1H), 6.97 (t, 1H), 7.26 (s, 1H), 7.78 (s, 1H), 8.19 (s, 1H), 8.90 (s,1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ = 395.2 184

δ ppm 2.37 (s, 3H), 3.33 (t, 2H), 4.56 (t, 2H), 4.74 (d, 2H), 6.73 (dd,1H), 6.98 (t, 1H), 7.85 (s, 1H), 7.96 (s, 1H), 8.75 (s, 1H), 8.94 (t,1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 445.1 185

δ ppm 3.35 (d, 2H), 4.56 (t, 2H), 4.77 (s, 2H), 6.72 (dd, 1H), 6.96 (t,1H), 8.55 (d, 1H), 8.59 (s, 1H), 8.80 (d, 1H), 8.85 (s, 1H), 9.15 (s,1H), 9.54 (s, 1H). LC-MS: [M + H]⁺ = 431.1 186

δ ppm 1.10 (d, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 3.24 (m, 2H), 3.87-3.92(m, 2H), 3.96-4.00 (m, 1H), 4.55 (t, 2H), 4.69 (s, 2H), 4.91 (d, 1H),6.72 (q, 1H), 6.96 (t, 1H), 7.47 (s, 1H), 8.53 (s, 1H), 9.42 (s, 1H).LC-MS: [M + H]⁺ = 438.2 187

δ ppm 1.10 (d, 3H), 2.08 (s, 3H), 2.17 (s, 3H), 3.35 (m, 2H), 3.89-3.93(m, 2H), 3.96-4.00 (m, 1H), 4.55 (t, 2H), 4.69 (d, 2H), 4.91 (d, 1H),6.71 (q, 1H), 6.96 (t, 1H), 7.47 (s, 1H), 8.53 (t, 1H), 9.43 (s, 1H).LC-MS: [M + H]⁺ = 438.2 188

δ ppm 1.41 (d, 6H), 2.36 (s, 3H), 3.30 (t, 2H), 4.54 (t, 2H), 4.59-4.63(m, 1H), 4.69 (s, 2H), 6.71 (q, 1H), 6.93 (t, 1H), 7.60 (s, 1H), 7.77(s, 1H), 8.58 (t, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 408.3 189

δ ppm 2.38 (s, 3H), 2.53 (s, 1H), 3.31 (t, 2H), 3.75 (t, 2H), 4.16 (t,2H), 4.57 (t, 2H), 4.70 (d, 2H), 6.71 (dd, 1H), 6.96 (t, 1H), 7.63 (s,1H), 7.79 (s, 1H), 8.57 (s, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 410.2190

δ ppm 2.36 (s, 3H), 3.30 (t, 3H), 3.75 (t, 2H), 4.12 (t, 2H), 4.55 (t,2H), 4.70 (d, 2H), 6.72 (dd, 1H), 6.96 (t, 1H), 7.74 (s, 1H), 8.32 (s,1H), 8.52 (s, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 410.2 191

δ ppm 3.37 (t, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.73 (dd, 1H), 6.90-7.21(m, 2H), 7.78 (s, 1H), 8.95 (s, 1H), 9.12 (s, 1H), 9.42 (s, 1H), 9.50(s, 1H). LC-MS: [M + H]⁺ = 414.1 192

δ ppm 0.84-0.86 (m, 2H), 0.95-0.97 (m, 2H), 3.30 (t, 2H), 3.77-3.80 (m,1H), 4.55 (t, 2H), 4.73 (d, 2H), 6.61 (d, 1H), 6.71 (q, 1H), 6.97 (t,1H), 7.47 (d, 1H), 7.93 (s, 1H), 8.83 (t, 1H), 9.49 (s, 1H). LC-MS: [M +H]⁺ = 392.2 193

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 3.32 (s, 2H), 4.56 (s, 2H), 4.73 (s,2H), 5.44 (d, 2H), 6.72 (dd, 1H), 6.97 (m, 1H), 7.55-7.57 (m, 1H), 7.69(s, 1H), 7.98 (d, 1H), 8.68 (dd, 1H), 8.79 (s, 1H), 9.48 (s, 1H). LC-MS:[M + H]+ = 395.1 194

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.18 (s, 3H), 2.46 (s, 3H), 3.35 (t,2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.96 (t, 1H), 7.27 (s,1H), 7.67 (s, 1H), 8.38 (s, 1H), 8.79 (s, 1H), 9.50 (s, 1H). LC-MS: [M +H]⁺ = 391.2 195

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.35 (s, 3H), 3.30 (t, 2H), 3.84 (s,3H), 4.55 (t, 2H), 4.71 (s, 2H), 6.72 (dd, 1H), 6.96 (t, 1H), 7.74 (s,1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 380.2196

¹H-NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, 3H), 2.18 (s, 3H), 3.34 (t,2H), 4.34 (dd, 2H), 4.57 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.78 (s,1H), 6.97 (t, 1H), 7.59 (s, 1H), 8.05 (s, 1H), 8.68 (s, 1H), 9.46 (s,1H). LC-MS: [M + H]⁺ = 421.3 197

¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H), 3.36 (t, 2H), 4.56 (t, 2H),4.73 (d, 2H), 6.73 (dd, 1H), 6.98 (t, 1H), 7.12 (s, 1H), 7.61-7.90 (m,2H), 8.18 (s, 1H), 8.77 (t, 1H), 9.48 (s, 1H). LC-MS: [M + H]⁺ = 443.1198

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H), 3.38 (t, 2H), 4.56 (t,2H), 4.74 (s, 2H), 6.72 (dd, 1H), 6.87-7.09 (m, 2H), 7.74 (s, 1H), 7.79(s, 1H), 8.66 (s, 1H), 8.88 (s, 1H), 9.50 (s, 1H). LC- MS: [M + H]⁺ =427.4 199

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 3.03 (d, 6H), 3.35 (t,2H), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd, 1H), 6.97 (t, 1H), 7.46 (d,1H), 7.71 (s, 1H), 7.87 (d, 1H), 8.76 (s, 1H), 9.49 (s, 1H). LC-MS: [M +H]⁺ = 448.2 200

δ ppm 3.34 (t, 2H), 3.87 (s, 3H), 4.55 (t, 2H), 4.72 (s, 2H), 6.71 (q,1H), 6.77 (s, 1H), 6.90 (s, 0.25H), 6.95 (t, 1H), 7.01 (s, 0.5H), 7.12(s, 0.25H), 7.83 (s, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 416.1 201

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.61 (s, 3H), 3.34 (t, 2H), 4.56 (t,2H), 4.73 (s, 2H), 6.71-6.99 (m, 3H), 7.55 (d, 1H), 7.59 (s, 1H), 7.89(d, 1H), 8.80 (s, 1H), 9.48 (s, 1H). LC-MS: [M + H]⁺ = 427.2 202

¹H NMR (400 MHz, CD₃OD) δ ppm 3.27 (t, 2H), 3.43 (d, 2H), 4.51 (t, 2H),4.71 (s, 2H), 6.63 (s, 1H), 6.89 (t, 1H), 8.35- 8.52 (m, 2H), 9.01 (s,1H), 9.97 (s, 1H) LC-MS: [M + H]⁺ = 363.9 203

¹H NMR (400 MHz, CD₃OD) δ ppm 2.08 (s, 3H), 2.24 (s, 3H), 4.58 (t, 2H),4.63- 4.73 (m, 2H), 6.72 (dd, 1H), 6.91-7.02 (m, 1H), 7.32 (dd, 1H),7.62 (dd, 1H), 8.51 (dd, 1H), 8.66 (s, 1H), 9.38 (s, 1H) LC-MS: [M + H]⁺= 390.9 204

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 3.30 (s, 2H), 4.56 (t,2H), 4.73 (s, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 7.36-7.38 (m, 2H), 7.72(s, 1H), 8.36 (dd, 1H), 8.82 (s, 1H), 9.48 (s, 1H). LC- MS: [M + H]⁺ =393.1 205

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.28 (t, 2H), 4.55 (t, 2H), 4.78 (s,2H), 6.72 (dd, 1H), 6.97 (t, 1H), 8.59 (d, 1H), 8.66 (s, 1H), 8.71 (t,1H), 9.07 (s, 1H), 9.56 (s, 1H), 9.93 (d, 1H); LC-MS: [M + H]⁺ = 364.1206

δ ppm 3.29 (br. s., 2H), 4.54 (t, J = 8.72 Hz, 2H), 4.74 (s, 2H), 6.70(dd, J = 3.86, 8.63 Hz, 1H), 6.95 (t, J = 9.44 Hz, 1H), 8.29 (s, 1H),9.11 (s, 1H), 9.43 (s, 1H), 9.53 (s, 2H). LC-MS: [M + H]⁺ = 363.9 208

¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.28 (s, 6H), 3.54 (s, 2H), 5.09 (s,2H), 7.05 (d, 1H), 7.31 (dt, 2H), 7.45 (t, 3H), 7.78 (d, 1H), 7.91 (d,2H), 7.95 (s, 1H), 9.30 (s, 1H). LC-MS: [M + H]⁺ = 398.9 209

δ ppm 2.29 (s, 3H), 2.46 (t, 4H), 3.19 (t, 4H), 5.00 (d, 2H), 7.01 (d,2H), 7.16 (dd, 1H), 7.30 (m, 2H), 7.52 (d, 1H), 7.91 (m, 4H), 8.82 (m,1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ = 440.2 210

δ ppm 1.34 (d, 3H), .1.69 (s, 4H), 2.34 (q, 2H), 3.25 (q, 3H), 5.04 (d,2H), 7.18 (m, 1H), 7.34 (m, 5H), 8.02 (m, 4H), 8.96 (t, 1H), 9.50 (s,1H). LC-MS: [M + H]⁺ = 439.3 211

δ ppm 2.23 (s, 3H), .2.41 (d, 4H), 3.54 (t, 4H), 5.02 (d, 2H), 6.95 (d,1H), 7.30 (m, 3H), 7.53 (d, 1H), 7.95 (s, 2H), 8.24 (q, 1H), 8.83 (m,2H), 9.49 (s, 1H). LC-MS: [M + H]⁺ = 441.2 212

δ ppm 2.23 (s, 3H), 2.43 (s, 4H), 3.53 (s, 4H), 5.04 (d, 2H), 7.17 (m,1H), 7.27 (m, 2H), 7.39 (dd, 1H), 7.53 (d, 1H), 7.74 (s, 1H), 8.01 (d,1H), 8.14 (d, 1H), 8.29 (s, 1H), 9.15 (t, 1H), 9.50 (s, 1H). LC-MS: [M +H]⁺ = 441.2 213

δ ppm 5.04 (s, 2H), 7.17 (m, 1H), 7.27 (m, 2H), 7.48 (m, 2H), 8.02 (d,1H), 8.15 (s, 1H), 8.49 (m, 2H), 9.08 (s, 1H), 9.28 (dd, 1H), 9.52 (s,1H). LC-MS: [M + H]⁺ = 343.2 214

δ ppm 3.26 (s, 3H), 5.06 (s, 2H), 7.19 (t, 1H), 7.32 (m, 2H), 7.54 (d,1H), 8.01 (m, 3H), 8.25 (s, 1H), 8.45 (d, 2H), 9.54 (s, 1H). LC-MS: [M +H]⁺ = 420.1 215

δ ppm 1.18 (d, 6H), 3.45 (m, 1H), 5.06 (s, 2H), 7.18 (d, 1H), 7.31 (m,2H), 7.54 (d, 1H), 7.91 (d, 2H), 8.02 (d, 1H), 8.26 (s, 1H), 8.45 (d,2H), 9.17 (s, 1H), 9.53 (s, 1H). LC-MS: [M + H]⁺ = 448.2 216

δ ppm 1.82 (m, 4H), 3.46 (m, 4H), 5.03 (s, 2H), 7.17 (dd, 1H), 7.29 (m,2H), 7.52 (d, 1H), 7.59 (d, 2H), 8.01 (d, 1H), 8.11 (s, 1H), 8.18 (d,2H), 9.03 (s, 1H), 9.48 (s, 1H). LC-MS: [M + H]⁺ = 439.2 217

δ ppm 5.04 (s, 2H), 7.18 (m, 1H), 7.34 (m, 3H), 7.47 (m, 2H), 7.54 (m,1H), 8.10 (m, 4H), 9.51 (s, 1H). LC-MS: [M + H]⁺ = 342.1 218

δ ppm 5.06 (s, 2H), 7.28 (t, 1H), 7.33 (m, 2H), 7.56 (d, 1H), 8.03 (d,1H), 8.23 (t, 2H), 8.37 (s, 1H), 8.63 (t, 3H), 9.53 (s, 1H). LC-MS: [M +H]⁺ = 343.1 219

¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.32 (s, 6H), 3.58 (s, 2H), 5.13 (s,2H), 7.06-7.18 (m, 2H), 7.40-7.54 (m, 3H), 7.84 (d, 1H), 7.94 (d, 2H),8.01 (s, 1H), 9.32 (s, 1H). LC-MS: [M + H]⁺ = 417.2 220

δ ppm 1.54 (q, 2H), 1.83 (t, 4H), 2.11 (s, 3H), 2.80 (d, 2H), 3.22 (t,1H), 5.06 (s, 2H), 7.19 (s, 1H), 7.31 (m, 2H), 7.54 (d, 1H), 7.90 (d,2H), 8.03 (d, 1H), 8.26 (s, 1H), 8.45 (d, 2H), 9.15 (s, 1H), 9.55 (s,1H). LC-MS: [M + H]⁺ = 503.2 221

δ ppm 9.53 (s, 2H), 9.43 (s, 1H), 9.11 (s, 1H), 8.29 (s, 1H), 6.95 (t,1H), 6.70 (dd, 1H), 4.74 (s, 2H), 4.54 (t, 2H), 3.29 (t, 2H). LC-MS:[M + H]⁺ = 363.9 222

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.19 (s, 3H), 2.48 (s, 3H), 3.34 (d,2H), 4.56 (t, 2H), 4.72 (d, 2H), 6.72 (dd, 1H), 6.96 (t, 1H), 7.23 (s,1H), 7.62 (s, 1H), 8.33 (s, 1H), 8.70 (t, 1H), 9.46 (s, 1H). LC-MS: [M +H]⁺ = 391.1. 223

¹H NMR (600 MHz, DMOS-d₆) δ ppm 2.23 (s, 6H) 2.38 (s, 3H) 2.50 (s, 7H)3.33-3.37 (m, 2H) 3.50-3.57 (m, 2H) 4.51-4.61 (m, 2H) 4.67-4.78 (m, 2H)6.69-6.76 (m, 1H) 6.92-7.00 (m, 1H) 7.29-7.37 (m, 1H) 7.61-7.68 (m, 1H)7.69-7.75 (m, 1H) 8.65-8.74 (m, 1H) 9.42-9.51 (m, 1H). LC-MS: [M + H]⁺ =434.2 224

δ ppm 1.27 (t, 3H), 2.21 (s, 3H), 2.76 (q, 2H), 3.34 (d, 2H), 4.56 (t,2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.94-7.00 (m, 1H), 7.24 (s, 1H), 7.63(s, 1H), 8.36 (s, 1H), 8.70 (s, 1H), 9.47 (s, 1H). LC-MS: [M + H]⁺ =405.2. 225

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.72-0.85 (m, 4H), 2.36 (s, 3H), 3.34(t, 2H), 4.35 (tt, 1H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.96(dd, 1H), 7.69 (s, 1H), 8.51 (s, 1H), 8.77 (s, 1H), 9.47 (s, 1H). LC-MS:[M + H]⁺ = 434.1 226

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (t, 3H), 2.35 (s, 3H), 3.34 (t,2H), 4.40 (q, 2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.92-7.00(m, 1H), 7.68 (s, 1H), 8.48 (s, 1H), 8.76 (s, 1H), 9.47 (s, 1H). LC-MS:[M + H]⁺ = 422.2 227

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.29-3.33 (m, 2H), 3.91 (s, 3H), 4.55(dd, 4H), 4.71 (d, 2H), 5.59 (t, 1H), 6.71 (dd, 1H), 6.95 (t, 1H), 7.76(s, 1H), 7.81 (s, 1H), 8.58 (t, 1H), 9.45 (s, 1H). LC- MS: [M + H]⁺ =396.1 228

δ ppm 2.24 (s, 3H), 4.56 (t, 2H), 4.73 (s, 2H), 6.73 (dd, 1H), 6.92-7.01(m, 1H), 7.58 (s, 1H), 7.79 (s, 1H), 8.38 (s, 1H), 9.50 (s, 1H). LC-MS:[M + H]⁺ = 410.8 229

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.26 (t, 3H). 2.37 (s, 3H), 2.77 (q,2H), 3.34 (s, 2H), 4.56 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.97 (t,1H), 7.18 (d, 1H), 7.68-7.58 (m, 2H), 8.70 (s, 1H), 9.47 (s, 1H). LC-MS:[M + H]⁺ = 405.3 230

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.04 (s, 3H), 3.31 (s, 2H), 3.93 (s,3H), 4.55 (t, 2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.99-6.92 (m, 1H), 7.02(d, 1H), 7.65 (s, 1H), 8.05 (d, 1H), 8.78 (s, 1H), 9.45 (s, 1H). LC-MS:[M + H]⁺ = 407.1 231

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.31 (s, 2H), 4.55 (t, 2H), 4.76 (s,2H), 6.72 (dd, 1H), 7.00-6.93 (m, 1H), 7.35- 7.31 (m, 1H), 7.92 (td,1H), 8.65 (d, 1H), 8.68 (s, 1H), 8.81 (d, 1H), 8.90 (s, 1H), 9.53 (s,1H). LC-MS: [M + H]⁺ = 363.1 232

δ ppm 2.38 (s, 3H), 3.32 (d, 2H), 4.56 (t, 2H), 4.74 (s, 2H), 6.71 (dd,1H), 6.96 (dd, 1H), 8.15 (s, 1H), 8.32-8.40 (m, 2H), 8.80 (s, 1H), 9.09(d, 1H), 9.46 (s, 1H). LC-MS: [M + H]⁺ = 376.9 233

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.19 (s, 3H), 3.31 (t, 2H), 4.55 (t,2H), 4.70 (s, 2H), 6.71 (dd, 1H), 6.93-6.98 (m, 1H), 7.53 (s, 1H), 7.99(s, 1H), 8.25 (d, 1H), 8.78 (s, 1H), 9.52 (s, 1H). LC- MS: [M + H]⁺ =366.1 234

δ ppm 3.25-3.34 (m, 2H), 4.55 (t, 2H), 4.62 (d, 2H), 4.74 (s, 2H), 5.48(t, 1H), 6.72 (dd, 1H), 6.96 (dd, 1H), 7.56 (d, 1H), 8.15 (s, 1H), 8.51(dd, 1H), 8.81 (s, 1H), 9.19 (dd, 1H), 9.51 (s, 1H). LC-MS: [M + H]⁺ =392.9 235

¹H NMR (400 MHz, Methanol-d₄) δ ppm 3.38 (d, 2H), 4.59 (t, 2H), 4.75 (d,2H), 6.66 (dd, 1H), 6.80-6.93 (m, 1H), 7.71 (d, 1H), 9.33 (d, 1H).LC-MS: [M + H]⁺ = 303.9 236

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.10 (s, 3H), 2.16 (s, 3H), 3.31 (s,2H), 4.56 (t, 2H), 4.70 (s, 2H), 6.72 (dd, 1H), 6.92 (s, 1H), 6.94-6.99(m, 1H), 7.78 (s, 1H), 8.88 (s, 1H), 9.50 (s, 1H). LC-MS: [M + H]⁺ =379.9 237

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.30 (d, 2H), 4.55 (t, 2H), 4.71 (s,2H), 6.56-6.60 (m, 1H), 6.71 (dd, 1H), 6.92- 6.99 (m, 1H), 7.78 (d, 1H),8.18 (s, 1H), 8.79 (d, 1H), 9.54 (s, 1H). LC-MS: [M + H]⁺ = 352.1 238

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.39 (s, 3H), 3.31 (d, 2H), 4.55 (t,2H), 4.72 (s, 2H), 6.72 (dd, 1H), 6.97 (t, 1H), 8.14 (s, 1H), 8.91 (s,1H), 9.22 (s, 1H), 9.56 (s, 1H). LC-MS: [M + H]⁺ = 367.1 239

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.14 (s, 3H), 3.30 (d, 2H), 4.54 (t,2H), 4.70 (s, 2H), 6.71 (dd, 1H), 6.93-6.99 (m, 1H), 7.59 (s, 1H), 8.13(s, 1H), 8.59 (s, 1H), 8.70 (s, 1H), 9.54 (s, 1H). LC- MS: [M + H]⁺ =366.1 240

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.31 (d, 2H), 4.54 (d, 2H), 4.71 (s,2H), 6.72 (s, 1H), 6.96 (s, 1H), 7.14 (s, 1H), 7.83 (s, 1H), 8.05 (s,1H), 8.36 (s, 1H), 8.83 (s, 1H), 9.53 (s, 1H). LC-MS: [M + H]⁺= 352.1241

¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.32 (t, 2H), 4.55 (t, 2H), 4.73 (d,2H), 6.72 (dd, 1H), 6.97 (t, 1H), 8.19 (s, 1H), 8.31 (s, 1H), 8.97 (s,1H), 9.34 (s, 1H), 9.57 (s, 1H). LC-MS: [M + H]⁺ = 353.1 242

¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.48 (s, 3H), 4.49-4.40 (m, 1H),4.61- 4.52 (m, 2H), 5.07 (d, 2H), 5.72 (d, 1H), 6.81 (dd, 1H), 7.12-6.98(m, 1H), 7.44- 7.36 (m, 1H, 7.66 (s, 1H), 7.83 (d, 1H), 8.51 (d, 1H),9.34 (s, 1H). LC-MS: [M + H]⁺ = 392.9 243

¹H NMR (400 MHz, Methanol-d₄) δ ppm 4.46 (dd, 1H), 4.59 (dd, 1H), 4.65(s, 2H), 4.86 (br s., 1H) 5.07 (d, 2H) 5.72 (d, 1H) 6.81 (dd, 1H) 7.06(t, 1H) 7.49 (dd, 1H) 7.75 (s, 1H) 7.89-7.96 (m, 1H) 8.64 (d, 1H) 9.34(s, 1H). LC-MS: [M + H]⁺ = 408.8 244

¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.41-2.50 (m, 3H) 4.46 (dd, 1H) 4.59(dd, 1H) 4.87 (br s., 1H) 5.08 (d, 1H) 5.68-5.76 (m, 1H) 6.81 (dd, 1H)7.06 (t, 1H) 7.50 (t, 1H) 7.64 (d, 1H) 7.75 (s, 1H) 8.46 (d, 1H) 9.34(s, 1H). LC-MS: [M + H]⁺ = 408.8 245

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 3.31 (t, 2H), 3.43 (s,3H), 4.45 (t, 2H), 4.70 (s, 2H), 6.53 (dd, 1H), 6.78-6.66 (m, 1H), 6.83(s, 1H), 7.52 (s, 1H), 9.11 (s, 1H). LC-MS: [M + H]⁺ = 379.9

VI. Pharmacology and Utility

As a key component of PRC2 complex, EED has no intrinsic enzymaticactivity. However, it is critical for proper PRC2 function. EED directlybinds to H3K27me3 and this binding event localizes the PRC2 complex tothe chromatin substrate and allosterically activates themethyltransferase activity. Targeting the allosteric site within theregulatory EED subunit of PRC2, may offer a novel and unique angle to beadvantageous to, or complementary to, directly targeting the SAMcompetition mechanism of EZH2 or PRC2. Therefore, targeting EEDrepresents a highly attractive strategy for the development of a noveltherapy for the treatment of many forms of cancers. In particular, theneed exists for small molecules that inhibit the activity of PRC2through targeting EED. It has now been found that triazolopyrimidinederivatives as presently disclosed are useful to target EED for thetreatment of EED or PRC2-mediated diseases or disorders, especiallycancers.

The utility of the compounds of the present invention may bedemonstrated using any one of the following test procedures. Compoundsof the present disclosure were assessed for their ability to inhibitPRC2 activity in a pentameric complex of EZH2, SUZ12, EED, Rbap48 andAEBP in biochemical assays. The ability of compounds of the presentdisclosure to inhibit cellular activity of PRC2 was assessed byanalysing histone H3 lysine 27 methylation in human cell lines. Theability of compounds of the present disclosure to inhibit cancers wasderived from their ability to modulate activity in human cancer celllines bearing specific dependence to PRC2 activity to maintain cancerousgrowth.

EED-H3K27Me3 Peptide Competition Binding Assay by AlphaScreen (α-Screen)

To assess the compounds potency in the EED-H3K27Me3 competition bindingassay, compounds were serially diluted 3-fold in DMSO to obtain a totalof twelve concentrations. Then compounds at each concentration (75 nL ofeach) were transferred by Mosquito into a 384-well Perkin ElmerProxiPlate 384 plus plates. 8 uL of solutions containing 30 nM EED(1-441)-His protein and 15 nM biotin-H3K27Me3 (19-33) peptide in thebuffer (25 mM HEPES, pH 8, 0.02% Tween-20, 0.5% BSA) were added to thewells and then incubated with compound for 20 min. AlphaScreen detectionbeads mix was prepared immediately before use by mixing nickel chelateacceptor beads and streptavidin donor beads in a 1:1 ratio (PerkinElmer, Product No. 6760619C/M/R) into the buffer described above. Then 4μL of detection beads mix was added to the plate and incubate in thedark at the rt for 1 h. The final concentration of donor and acceptorbeads was 10 μg/mL for each. Plates were read on EnVision (PerkinElmer)using the AlphaScreen setting adapted for optimal signal detection witha 615 nm filter, after sample excitation at 680 nm. The emission signalat 615 nm was used to quantify compounds inhibition. AlphaScreen signalswere normalized based on the reading coming from the positive (maximumsignal control) and negative controls (minimum signal control) to givepercentage of activities left. The data were then fit to a dose responseequation using the program Helios (Novartis) to get the IC50 values.Helios is a Novartis in-house assay data analysis software using themethods described by Normolle, D. P., Statistics in Medicine,12:2025-2042 (1993); Formenko, I. et al, Computer Methods and Programsin Biomedicine, 82, 31-37 (2006); Sebaugh, J. L., PharmaceuticalStatistics, 10:128-134 (2011); Kelly, C. et al., Biometrics,46(4):1071-1085 (1990); and Kahm, M. et al., Journal of StatisticalSoftware, 33 (7): (2010) (grofit: Fitting Biological Growth Curves withR, pages 1-21, available at http://www.jstatsoft.org/).

Each compound was counterscreened to determine if it interfered with theAlphaScreen beads. Compounds were diluted as described in the precedingsection, and the assay was performed by adding 12 μL of 10 nMbiotin-miniPEG-His6 peptide in the above buffer and incubating for 20min at rt prior to addition of the beads to 10 μg/mL each. The plateswere then incubated for 1 h at rt in dark before being read on EnVison.

EED LC-MS Assay

Representative compounds of the present disclosure were serially andseparately diluted 3-fold in DMSO to obtain a total of eight or twelveconcentrations. Then the test compounds at each concentration (120 nL ofeach) were transferred by Mosquito into a 384-well Perkin ElmerProxiPlate 384 plus plates. Solutions (6 μL) of 24 nM the wild type PRC2(wtPRC2) complex and 2 μM SAM in reaction buffer (20 mM Tris, pH 8.0,0.1% BSA, 0.01% Triton, 0.5 mM DTT) were added to the wells that werethen incubated with the test compound for 20 min. A 6 μL solution of 3μM of the peptide substrate H3K27Me0 (histone H3[21-44]-biotin) inreaction buffer was added to initiate each reaction. The finalcomponents in the reaction solution include 12 nM wtPRC2 complex, 1 μMSAM, and 1.5 μM H3K27me0 peptide with varying concentration of thecompounds. A positive control consisted of the enzyme, 1 μM SAM and 1.5μM substrate in the absence of the test compound, and a negative controlconsisted of 1 μM SAM and 1.5 μM substrate only. Each reaction wasincubated at rt for 120 min, then stopped by addition of 3 μL per ofquench solution (2.5% TFA with 320 nM d4-SAH). The reaction mixture wascentrifuged (Eppendorf centrifuge 5810, Rotor A-4-62) for 2 min at 2000rpm and read on an API 4000 triple quadrupole mass spec with TurbulonSpray (Applied Biosystem) coupled with Prominence UFLC (Shimadzu). Thelevels of SAH production were then normalized based on the values comingfrom the positive and negative controls to give percent enzymeactivities. The data were then fit to a dose response equation using theprogram Helios to get the IC₅₀ values of the test compound.

ELISA (H3K27 Methylation) Assay

Representative compounds of the present disclosure were serially andseparately diluted 3-fold in DMSO to obtain a total of eight or twelveconcentrations. Then the compounds were added to G401 cell cultured in384-well plate at 1:500 dilution to obtain the highest concentration of20 μM. The cells were further cultured for 48 h before ELISA procedure.

Histone extraction: Cells, in 384-well plate, were washed with PBS(10×PBS buffer (80 g NaCl (Sigma, S3014), 2 g KCl (Sigma, 60128), 14.4 gNa₂HPO₄ (Sigma, S5136), 2.4 g KH₂PO₄ (Sigma, P9791) to 1 L water, pH to7.4) and lysed with the addition of lysis buffer (0.4N HCl; 45 μL perwell). The plate was gently agitated at 4° C. for 30 min. The celllysate was neutralized with neutralization buffer (0.5 M sodiumphosphate dibasic, pH 12.5, 1 mM DTT; 36 μL per well). The plate wasagitated to ensure the lysates were well mixed prior to the ELISAprotocol.

ELISA protocol: Cell lysates were transferred to the wells of a 384-wellplate and the final volume was adjusted to 50 μL per well with PBS. Theplate was sealed, centrifuged at 2,000 rpm for 2 min and incubated at 4°C. for about 16 h. The plate was washed with TBST buffer (1×TBS (10×TBS:24.2 g Tris (Sigma, T6066), 80 g NaCl (Sigma, S3014) to 1 L of water andadjust pH to 7.6 with HCl) with 0.1% Tween-20). Blocking buffer (TBST,5% BSA; 50 μL per well) was added and the plate was incubated for 1 h atrt. The blocking buffer was removed and primary antibody was added (30μL per well). The following dilutions were performed with blockingbuffer: for anti-H3K27me3 antibody (Cell Signaling Technology, #9733),dilution was 1:1000; for anti-H3K27me2 antibody (Cell SignalingTechnology, #9288), dilution was 1:100; for anti-H3 antibody (Abcam, Cat#24834), dilution was 1:1000. The primary antibody was incubated in theplate at rt for 1 h. The wells were washed with TBST and incubated withsecondary antibody for 1 h at rt. For secondary antibodies, thefollowing dilutions were carried out with blocking buffer: anti-rabbitantibody (Jackson ImmunoResearch, #111-035-003), dilution was 1:2000;and anti-mouse antibody (Cell signaling technology, #7076), dilution was1:1000. After 1 h of incubation at rt, the wells were washed with TBST.ECL substrate (Pierce, #34080) was added at 30 μL per well and theplates were centrifuged at 2,000 rpm for 2 min. The signal was readusing a PerkinElmer Envision Reader. The H3K27 methylation readouts werenormalized using H3 signal and then percentage inhibition was calculatedagainst the samples treated with DMSO. The data were then fit to a doseresponse curve using the program Helios to get the IC₅₀ values of thetest compound.

Western Blot Analysis

Representative compounds of the present disclosure were analyzed fortheir ability to selectively inhibit PRC2. Western blot was performedusing standard molecular biology techniques. Cell was lysed in SDS lysisbuffer (Millipore, Cat #20-163) and protein concentration was measuredby BCA protein assay (Pierce, Cat #PI-23221). Antibodies for westernblots: anti-EZH2 (#3147), anti-H3 (#9715), anti-H3K4me1 (#9723),anti-H3K4me2 (#9725), anti-H3K4me3 (#9727), anti-H3K9me2 (#9753),anti-H3K36me2 (#9758), anti-H3K27me2 (#9755), and anti-H3K27me3 (#9756)were purchased from Cell Signaling Technology (Danvers, Mass., USA).Anti-H3K9me1 (#07-395), anti-H3K27me1 (#07-448), and anti-H3K36me1(#07-548) were purchased from Millipore (Billerica, Mass., USA).Anti-H3K36me3 (ab9050-100) was purchased from Abcam (Cambridge, UK).Anti-H3K9me3 (#39161) was purchased from Active Motif (Carlsbad, Calif.,USA).

Compounds of the present disclosure specifically inhibit the methylationof the PRC2 substrate H3K27. This can be demonstrated by their abilityto inhibit H3K27me2 and H3K27me3 in a number of human cancer cell lines,examples include rhabdoid cells (G401) and lymphoma cells (WSU-DLCL2,KARPAS422, SU-DHL4). Selectivity is profiled against a number of othermethylation marks, for example: H3K4me2; H3K9me2; H3K36me3; andH3K79me3.

Analysis of Cell Proliferation

B cell lymphoma cell KARPAS422 was cultured using standard cell cultureconditions in RPMI-1640 (Invitrogen, cat #11875) supplemented with 15%FBS (Invitrogen, cat #10099-141) in humidified incubator at 37° C., 5%CO₂. To assess the effect of PRC2 inhibition on cell proliferation,exponentially growing cells were seeded at a density of 1×10⁵ cells/mLin 12-well plate (Corning, cat #CLS3513). After cell seeding, a compoundof the present disclosure was added to the cell media (in concentrationsranging from 0 to 100 μM, 3× dilution series). Viable cell numbers weredetermined every 3-4 days for up to 14 days using Vi-CELL (BeckmanCoulter). On days of cell counting, fresh growth media and compound werereplenished and cells split back to a density of 1×10⁵ cells/mL. Totalcell number is expressed as split-adjusted viable cells per mL. The doseresponse curves and IC₅₀ values were generated using Prism.

Analysis of Pharmacokinetic Properties

Pharmacokinetic properties of the compounds as presently disclosed canbe determined by using the below described protocol.

A representative compound of the present disclosure was dissolved in 10%PEG300, 10% Solutol HS 15 and 80% pH 4.65 Acetate buffer to yield afinal concentration of 0.2 mg/mL for intravenous (IV) and oraladministration (PO).

For rat PK studies, a total of three male Sprague Dawley rats each wereused for rat IV and PO PK study, respectively. The formulation solutionwas administered via a single bolus IV at 1 mg/kg and a single oralgavage (PO) at 2 mg/kg, respectively. Blood samples (approximately 150μL) were collected via jugular cannula at appropriate time points.

For mouse PK study, a total of twelve male ICR mice were used for IV andPO study, respectively. The formulation solution was administered via asingle bolus IV at 1 mg/kg and a single oral gavage (PO) at 2 mg/kg,respectively. Blood samples (approximately 150 μL) were collected viaretro-orbital puncture (˜150 μL/mouse) after anesthetized by isofluraneor via cardiac puncture (terminal collection) at appropriate time points(n=3).

Samples were collected in tubes containing K3-EDTA and stored on iceuntil centrifuged. The blood samples were centrifuged at approximately8000 rpm for 6 min at 2-8° C. and the resulting plasma was separated andstored frozen at approximately −80° C. After adding the internalstandard, the plasma samples were quantified by LC-MS/MS using thecalibration curve. PK parameters including area under concentrationcurve (AUC), mean residence time (MRT), plasma clearance (Cl), steadystate volume of distribution (Vdss), elimination half-life (t_(1/2)),maximum concentration (Cmax), time of maximum concentration (Tmax) andoral bioavailability (F %) were calculated using the followingequations:

AUC = ∫₀^(∞)Cdt${MRT} = {\frac{\int_{0}^{\infty}{{tC}{dt}}}{\int_{0}^{\infty}{C{dt}}} = \frac{AUMC}{AUC}}$

t is time and C is plasma concentration at the time (t);Dose_(iv) is the dose for intravenous administration; and Dose_(oral) isthe dose for oral administration.Cl=Dose iv/AUCt_(1/2)=0.693×MRT

Vdss=Cl*MRT

F %=(Dose_(iv)×AUC_(oral))/Dose_(oral)×AUC_(iv))×100%

Protocol for High-Throughput Equilibrium Solubility Assay

Compounds of the present disclosure were first solubilized at 10 mM inpure DMSO. 20 μL each of the DMSO stock solution was then transferredinto 6 wells on 96-well plate. The DMSO solvent was dried with GeneVacsolvent evaporator at 30° C., 1 mbar vacuum for 1 h. After the additionof 200 μL of buffer solutions (pH 6.8, or FaSSIF), the plate was sealedand shaken at 160 rpm for 24 h at rt. The plate was centrifuged at 3750rpm for 20 min, 5 μL of supernatant is mixed with 495 μL of MeOH/H₂O(1:1). 0.01 μM, 0.1 μM, 1 μM, 10 μM stock solutions were prepared byseries of dilution for the calibration curves. The supernatant wasquantified by HPLC or LC/MS using the calibration curve. High-Throughputequilibrium solubility was determined based on the concentration of thesupernatant.

Efficacy Studies in Mouse Xenograph Model

All experiments conducted were performed in female athymic Nude-nu micein an AAALAC certificated facility. The animals were kept under SPFconditions in individual ventilation cages at constant temperature andhumidity (i.e., 20-26° C.; 40-70%) with 5 or less animals in each cage.Animals had free access to irradiation sterilized dry granule food andsterile drinking water. All procedures and protocols were approved bythe Institutional Animal Care and Use and interal committee.

The cells Karpas 422 human B cell lymphoma were cultured in RPMI-1640medium (Gibco; 11875-093) supplemented with 15% FBS (Gibco; 10099-141)and 1% Pen Strep (Gibco; 15140-122) at 37° C. in an atmosphere of 5% CO₂in air. Cells were maintained in suspension cultures at concentrationsbetween 0.5-2×10⁶ cells/ml. Cells were split at 1:3 every 2-4 days. Toestablish xenograft tumor models the cells were collected, suspended inPBS, mixed with Matrigel (BD Bioscience) at a volume ratio of 1:1 at aconcentration of 1×10⁸ cells/mL and then injected subcutaneously intothe right flank of balb/c nude mice (Vital River) at a concentration of5×10⁶ cells per animal.

The compound was formulated as a suspension in 0.5% methyl cellulose(MC) and 0.5% Tween 80 in 50 mM pH6.8 buffer (prepared in houseaccording to the USP) and administered orally by gavage at specificdoses.

Treatment was initiated when the average tumor volume reached 100-300mm³. Tumor growth and body weights were monitored at regular intervals.The two largest diameters, width (W) and length (L), of the xenografttumors were measured manually with calipers and the tumor volume wasestimated using the formula: 0.5×L×W².

When applicable, results are presented as mean±SEM. Graphing andstatistical analysis was performed using GraphPad Prism 5.00 (GraphPadSoftware). Tumor and body weight change data were analyzedstatistically. If the variances in the data were normally distributed(Bartlett's test for equal variances), the data were analyzed usingone-way ANOVA with post hoc Dunnet's test for comparison of treatmentversus control group. The post hoc Tukey test was used for intragroupcomparison. Otherwise, the Kruskal-Wallis ranked test post hoc Dunn'swas used.

As a measure of efficacy the % T/C value is calculated at the end of theexperiment according to:

(Δtumor volume^(treated)/Δtumor volume^(control))*100

Tumor regression was calculated according to:

−(Δtumor volume^(treated)/tumor volume^(treated at start))*100

Where Δtumor volumes represent the mean tumor volume on the evaluationday minus the mean tumor volume at the start of the experiment.

The exemplified Examples disclosed below were tested in the EEDAlphascreen binding, LC-MS and/or ELISA assays described above and foundhaving EED inhibitory activity. A range of IC₅₀ values of ≤5 μM (5000nM) was observed.

Table 3 below lists IC₅₀ values in the EED (a) Alphascreen bindingQualified, (b) LC-MS Qualified and/or (c) ELISA Qualified assaysmeasured for the following examples. “N/A” stands for “not assessed”.

TABLE 3 (a) (b) (c) Ex IC₅₀ IC₅₀ IC₅₀ # IUPAC name (μM) (μM) (μM) 18-(1,3-dimethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0041 0.0082 0.0009 [4,3-c]pyrimidin-5-amine 2N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo0.0059 0.0089 0.0026 [4,3-c]pyrimidin-5-amine 38-(2,4-dimethylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0038 0.0064 0.0034 [4,3-c]pyrimidin-5-amine 4N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-0.0032 0.0039 0.0021 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-4-methylpyridin-3-yl)-[1,2,4]triazolo0.0048 0.0097 0.0029 [4,3-c]pyrimidin-5-amine 68-(6-cyclopropyl-2-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0052 0.0077 0.0038 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 7(3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0048 0.0093 0.0052 pyridin-2-yl)methanol 88-(2-cyclopropyl-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0049 0.0072 0.0029 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 9N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-isopropoxy-4-methylpyrimidin-5-yl)-0.0041 0.0079 0.0035 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 103-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0073 0.0138 0.001 pyridine 1-oxide 11N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-((dimethylamino)methyl)phenyl)-[1,2,4]triazolo0.0069 0.02 0.0144 [4,3-c]pyrimidin-5-amine 12N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo0.0079 0.0159 0.0176 [4,3-c]pyrimidin-5-amine 13N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0536 0.0477 0.1393 14N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-[1,2,4]triazolo0.0078 0.0128 0.0274 [4,3-c]pyrimidin-5-amine 154-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-0.0128 0.0206 0.0198 dimethylbenzenesulfonamide 16N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0108 0.024 0.0604 17N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0115 0.017 0.0315 18N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-0.0185 0.0279 N/A [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 19N-(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0189 0.0192 0.0401 phenyl)methanesulfonamide 20N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-0.0144 0.0171 0.0783 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 21N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-0.0252 0.026 0.1503 5-amine 228-(4-((dimethylamino)methyl)phenyl)-N-((2-methyl-2,3-dihydrobenzofuran-4-yl)methyl)-1.9822 1.8195 N/A [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 238-(4-((dimethylamino)methyl)phenyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0311 0.0257 0.0424 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 24N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-[1,2,4]triazolo0.0304 0.037 0.162 [4,3-c]pyrimidin-5-amine 25N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo0.0307 0.0449 0.4061 [4,3-c]pyrimidin-5-amine 26N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-4-(methylsulfonyl)phenyl)-[1,2,4]triazolo0.0099 0.0171 0.0448 [4,3-c]pyrimidin-5-amine 27N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo0.0199 0.0472 0.3655 [4,3-c]pyrimidin-5-amine 28N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methylsulfonyl)pyridin-3-yl)-[1,2,4]triazolo0.0111 0.0276 0.4153 [4,3-c]pyrimidin-5-amine 29N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(piperidin-4-ylsulfonyl)phenyl)-[1,2,4]triazolo0.0081 0.0145 0.214 [4,3-c]pyrimidin-5-amine 30N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-[1,2,4]triazolo0.0053 0.0248 0.069 [4,3-c]pyrimidin-5-amine 31N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0302 0.0215 0.0298 328-(2-chlorophenyl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0434 0.0229 0.1154 33N-(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0285 0.0175 0.2974 2-fluorophenyl)methanesulfonamide 342-(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]trizaolo[4,3-c]pyrimidin-8-yl)-0.0375 0.0494 1.9507 1H-pyrazol-1-yl)ethanol 35N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(2-(dimethylamino)ethyl)phenyl)-[1,2,4]triazolo0.0083 0.0153 0.0334 [4,3-c]pyrimidin-5-amine 36N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-0.0185 0.0224 0.0683 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 37N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[4,3-c]0.0123 0.0207 0.0134 pyrimidin-5-amine 382-(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0242 0.0349 0.2017 phenoxy)ethanol 39N-(2-fluoro-4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]0.0178 0.0175 0.0227 pyrimidin-8-yl)phenyl)methanesulfonamide 404-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-0.0562 0.0566 1.3368 hydroxyethypenzenesulfonamide 41(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0132 0.0097 0.3748 phenyl)(piperazin-1-yl)methanone 424-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-0.0525 0.0861 0.2203 dimethylbenzamide 433-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-0.0309 0.0331 0.2471 dimethylbenzamide 44N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-3-yl)-[1,2,4]0.0128 0.0192 0.0097 triazolo[4,3-c]pyrimidin-5-amine 45N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]0.02 0.0328 0.0086 triazolo[4,3-c]pyrimidin-5-amine 46N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-0.0435 0.064 0.0048 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 47N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoropyridin-3-yl)-[1,2,4]-0.0052 0.0049 0.0103 triazolo[4,3-c]pyrimidin-5-amine 488-(6-aminopyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0129 0.0302 0.2606 [4,3-c]pyrimidin-5-amine 494-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,2-0.0125 0.0128 0.3662 trimethylbenzamide 508-(4-chloropyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.0191 0.0412 0.1198 triazolo[4,3-c]pyrimidin-5-amine 51N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.136 0.3458 N/A amine 52N4(2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0709 0.047 0.1061 amine 53N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-(dimethylamino)ethyl)pyridin-3-yl)-0.0124 0.0287 0.141 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 54N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyrimidin-5-yl)-[1,2,4]triazolo[4,3-c]0.0291 0.0546 0.1439 pyrimidin-5-amine 554-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0211 0.0318 0.0131 N,N-dimethylbenzamide 56N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methylsulfonyl)pyridin-3-yl)-[1,2,4]0.0196 0.0309 0.0493 triazolo[4,3-c]pyrimidin-5-amine 57N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]0.0084 0.0186 0.0334 pyrimidin-5-amine 588-(6-amino-4-fluoropyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]0.0063 0.013 0.1241 pyrimidin-5-amine 59N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(3,5-dimethylisoxazol-4-yl)-[1,2,4]triazolo[4,3-c]0.0318 0.0387 0.086 pyrimidin-5-amine 60N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyrimidin-5-yl)-[1,2,4]0.0195 0.047 0.2994 triazolo[4,3-c]pyrimidin-5-amine 61N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(dimethylamino)pyridin-3-yl)-[1,2,4]triazolo0.0129 0.0197 0.1754 [4,3-c]pyrimidin-5-amine 625-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)picolinonitrile0.016 0.0294 0.3394 63N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-ethoxypyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0756 0.0686 0.1984 amine 64N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,5-dimethyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-c]0.0124 0.0413 0.0978 pyrimidin-5-amine 658-(6-cyclopropylpyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]0.0183 0.02 0.1096 pyrimidin-5-amine 66N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-0.0156 0.0447 0.0803 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 672-(4-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0309 0.0902 0.5206 3,5-dimethyl-1H-pyrazol-1-yl)ethanol 68(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)0.0197 0.0367 0.378 (morpholino)methanone 69N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-morpholinopyridin-3-yl)-[1,2,4]triazolo[4,3-c]0.182 0.3769 N/A pyrimidin-5-amine 70N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-6-(methylsulfonyl)pyridin-3-yl)-0.0115 0.0211 0.0839 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 718-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.009 0.0189 0.0426 [4,3-c]pyrimidin-5-amine 72(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0093 0.0175 0.0097 phenyl)(4-methylpiperazin-1-yl)methanone 73N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-6-morpholinopyridin-3-yl)-[1,2,4]triazolo0.0125 0.0174 0.3317 [4,3-c]pyrimidin-5-amine 74N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2,6-dimethylmorpholino)pyridin-3-yl)-[1,2,4]triazolo0.0896 0.1391 N/A [4,3-c]pyrimidin-5-amine 75N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(2-(methylsulfonyl)ethoxy)phenyl)-[1,2,4]triazolo0.034 0.0375 0.2981 [4,3-c]pyrimidin-5-amine 768-(4-aminopyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0275 0.0569 0.3196 [4,3-c]pyrimidin-5-amine 77N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo0.0216 0.0523 0.581 [4,3-c]pyrimidin-5-amine 788-(6-(difluoromethoxy)pyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.1034 0.1598 N/A [4,3-c]pyrimidin-5-amine 795-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-0.0575 0.1029 N/A methylpicolinamide 80(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)0.0037 0.0088 0.1315 (pyrrolidin-1-yl)methanone 81N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-thiomorpholinopyridin-3-yl)-[1,2,4]triazolo0.0146 0.0191 0.1554 [4,3-c]pyrimidin-5-amine 82N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-0.0167 0.0309 0.1072 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 83N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(methoxymethyl)-5-methylpyridin-3-yl)-0.0105 0.0228 0.1402 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 841-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0063 0.0129 0.1478 pyridin-2-yl)ethanol 85N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0083 0.026 0.0333 amine 86N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-methoxyethyl)pyridin-3-yl)-[1,2,4]triazolo0.0111 0.0267 0.0758 [4,3-c]pyrimidin-5-amine 871-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0418 0.0839 0.7071 pyridin-3-yl)pyrrolidin-2-one 88N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(dimethylamino)pyrimidin-5-yl)-[1,2,4]triazolo0.0257 0.0347 0.2375 [4,3-c]pyrimidin-5-amine 89N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-(2-(dimethylamino)ethyl)phenyl)-[1,2,4]triazolo0.0045 0.0103 0.1009 [4,3-c]pyrimidin-5-amine 90N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)-0.0131 0.0303 0.6753 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 91N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-thiomorpholinopyridin-3-yl)-[1,2,4]triazolo0.0099 0.0153 0.0225 [4,3-c]pyrimidin-5-amine 92N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-morpholinopyridin-3-yl)-[1,2,4]triazolo0.0192 0.0515 0.0409 [4,3-c]pyrimidin-5-amine 935-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0079 0.0125 0.0241 picolinonitrile 94N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0113 0.0186 0.0257 amine 955-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-0.0052 0.0128 0.1581 dimethylpicolinamide 96N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(2-methylpyrrolidin-1-yl)pyridin-3-yl)-0.026 0.0132 0.3286 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 97 methyl4-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0061 0.0086 0.1828 pyridin-2-yl)piperazine-1-carboxylate 98N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(3-(methylsulfonyl)propoxy)pyridin-3-yl)-0.0217 0.0356 1.4173 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 992-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0042 0.0067 0.1075 pyridin-2-yl)propan-2-ol 1008-(6-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)pyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-0.014 0.0315 0.181 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 101N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridin-3-yl)-0.0117 0.0136 0.7614 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1025-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-(2-0.0339 0.0688 0.285 (dimethylamino)ethyl)-N-methylpicolinamide 103N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)-0.7284 0.4306 N/A [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1044-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0096 0.012 2.3341 pyridin-2-yl)piperazin-2-one 1054-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0269 0.0326 2.4238 3-methylpyridin-2-yl)piperazin-2-one 106N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-(methylsulfonyl)ethoxy)pyridin-3-yl)-0.025 0.0341 2.6999 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1074-(2-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0124 0.025 0.1612 pyridin-2-yl)ethyl)piperazine-1-carbaldehyde 1081-(4-(2-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0067 0.011 0.1734 pyridin-2-yl)ethyl)piperazin-1-yl)ethanone 1094-(2-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-0.0088 0.0137 1.2085 yl)pyridin-2-yl)ethyl)piperazin-2-one 1102-(4-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-0.0093 0.0152 0.1239 yl)pyridin-2-yl)piperazin-1-yl)ethanol 111N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoro-6-(methylamino)pyridin-3-yl)-[1,2,4]triazolo0.019 0.0174 0.1395 [4,3-c]pyrimidin-5-amine 112N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(dimethylamino)-4-fluoropyridin-3-yl)-0.0177 0.0176 0.3889 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1134-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0127 0.0157 0.7202 pyridin-2-yl)-1,4-diazepane-1-carbaldehyde 1145-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N-0.0154 0.0186 1.9792 ethylpicolinamide 115N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoropyridin-3-yl)-0.0047 0.0069 0.0243 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 116N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[4,3-c]0.0047 0.0076 0.0072 pyrimidin-5-amine 1173-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0235 0.0294 0.4803 pyridin-2-yl)oxazolidin-2-one 118N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]0.0101 0.0182 0.0177 pyrimidin-5-amine 1198-(6-cyclopropylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.004 0.0066 0.0108 [4,3-c]pyrimidin-5-amine 120N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-morpholinopyridin-4-yl)-[1,2,4]triazolo0.0156 0.0256 0.0721 [4,3-c]pyrimidin-5-amine 1212-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0134 0.0221 0.0142 benzonitrile 1222-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0192 0.0437 0.1354 benzamide 123N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]0.0123 0.0234 0.0197 pyrimidin-5-amine 1248-(4-chloropyridin-3-yl)-N4(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.01 0.0154 0.006 [4,3-c]pyrimidin-5-amine 1251-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0085 0.0234 N/A pyridin-2-yl)piperazin-2-one 1261-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0129 0.0172 0.6559 pyridin-2-yl)azetidin-3-ol 127N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-0.0026 0.0088 0.028 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 128N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)-0.0086 0.0165 0.0037 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 129(5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0039 0.0084 0.0019 pyridin-2-yl)(pyrrolidin-l-yl)methanone 130(5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.005 0.0137 0.0013 4-methylpyridin-2-yl)(pyrrolidin-l-yl)methanone 1315-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.004 0.0106 0.0033 N,N,4-trimethylpicolinamide 132N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-0.0062 0.0102 0.0077 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1334-((5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-0.0087 0.0223 0.1422 yl)pyridin-2-yl)methyl)piperazin-2-one 1344-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0173 0.0305 0.1648 pyridin-2-yl)piperazine-1-carbaldehyde 1353-(5-(5-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0057 0.0112 0.3214 pyridin-2-yl)-N,N-dimethylpropanamide 136N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-(trifluoromethyl)pyridin-3-yl)-0.0159 0.0418 0.0804 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 137N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(methoxymethyl)-6-methylpyridin-3-yl)-0.022 0.0296 0.2263 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1388-(4-chloro-6-methoxypyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0019 0.0084 0.0072 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 139N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-0.0017 0.006 0.0016 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1405-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0127 0.0551 0.0263 N,N-dimethylpicolinamide 141N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyridin-3-yl)-[1,2,4]triazolo0.0171 0.042 0.0351 [4,3-c]pyrimidin-5-amine 142N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxypyridin-3-yl)-[1,2,4]triazolo0.0024 0.0051 0.0043 [4,3-c]pyrimidin-5-amine 1438-(1-ethyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0181 0.0315 0.0106 [4,3-c]pyrimidin-5-amine 144N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-1H-pyrazol-5-yl)-[1,2,4]triazolo0.0063 0.0178 0.0683 [4,3-c]pyrimidin-5-amine 145N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyridin-4-yl)-[1,2,4]triazolo0.0024 0.0118 0.0052 [4,3-c]pyrimidin-5-amine 1468-(2,4-dichlorophenyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.023 0.0382 0.0744 [4,3-c]pyrimidin-5-amine 147N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo0.0036 0.0159 0.0113 [4,3-c]pyrimidin-5-amine 148N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-0.0052 0.018 0.0252 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1498-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0169 0.0337 0.2202 [4,3-c]pyrimidin-5-amine 1508-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0045 0.007 0.0148 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 151N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-0.0131 0.0216 0.0086 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 152N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo0.0055 0.0069 0.008 [4,3-c]pyrimidin-5-amine 153N-((2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-0.0078 0.0148 0.0073 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1548-(6-(difluoromethyl)pyridin-3-yl)-N-((2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0201 0.0369 0.0968 [4,3-c]pyrimidin-5-amine 155N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-2-methylpyridin-3-yl)-[1,2,4]0.017 0.0453 0.078 triazolo[4,3-c]pyrimidin-5-amine 1568-(6-amino-2-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.004 0.0173 0.0261 triazolo[4,3-c]pyrimidin-5-amine 1578-(2-chloro-4-fluorophenyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0223 0.0463 0.4454 [4,3-c]pyrimidin-5-amine 1582-(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0051 0.0096 0.0067 3,5-dimethyl-1H-pyrazol-1-yl)ethanol 159N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-(2-methoxyethyl)-0.005 0.0103 N/A3,5-dimethyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine160N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-(trifluoromethyl)pyridin-3-yl)-[1,2,4]triazolo0.0059 0.0113 N/A [4,3-c]pyrimidin-5-amine 161N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoro-6-methoxypyridin-3-yl)-[1,2,4]triazolo0.0036 0.0098 N/A [4,3-c]pyrimidin-5-amine 1628-(3-chloropyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0057 0.0211 0.0273 [4,3-c]pyrimidin-5-amine 163N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo0.0041 0.0109 N/A [4,3-c]pyrimidin-5-amine 164N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-[1,2,4]triazolo0.0042 0.0139 N/A [4,3-c]pyrimidin-5-amine 165N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-fluoro-2-methylphenyl)-[1,2,4]triazolo0.0045 0.0074 N/A [4,3-c]pyrimidin-5-amine 166N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)pyridin-3-yl)-[1,2,4]triazolo0.0111 0.031 0.0266 [4,3-c]pyrimidin-5-amine 1678-(2,6-dimethylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0033 0.0052 0.0393 [4,3-c]pyrimidin-5-amine 1688-(2-(difluoromethyl)pyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0046 0.0112 0.002 [4,3-c]pyrimidin-5-amine 169N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo0.0045 0.0066 0.0029 [4,3-c]pyrimidin-5-amine 170N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-0.0107 0.0121 0.0232 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 171N-((5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.006 0.0073 0.0265 pyridin-2-yl)methyl)acetamide 1728-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0066 0.0071 0.0044 [4,3-c]pyrimidin-5-amine 1738-(6-cyclopropyl-4-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0075 0.0077 0.0152 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 174N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxypyrimidin-5-yl)-[1,2,4]triazolo0.0047 0.0062 0.0042 [4,3-c]pyrimidin-5-amine 175N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxy-4-methylpyrimidin-5-yl)-0.0063 0.0092 0.0034 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 176N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methylpyrimidin-5-yl)-[1,2,4]triazolo0.0059 0.0083 0.0046 [4,3-c]pyrimidin-5-amine 1778-(2,3-dimethylpyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0038 0.0044 0.0044 [4,3-c]pyrimidin-5-amine 1784-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0054 0.007 0.0114 3-methylbenzonitrile 1798-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0124 0.0161 0.0091 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 180N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-3-methylpyridin-4-yl)-[1,2,4]triazolo0.0073 0.0079 0.0124 [4,3-c]pyrimidin-5-amine 1818-(2-(difluoromethyl)-3-methylpyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0026 0.006 0.0208 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 182N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(fluoromethyl)-3-methylpyridin-4-yl)-0.0031 0.0056 0.0025 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 183N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-fluoro-5-methylpyridin-4-yl)-[1,2,4]triazolo0.0048 0.0081 0.0106 [4,3-c]pyrimidin-5-amine 184N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-2-(trifluoromethyl)pyridin-4-yl)-0.0054 0.0132 0.0777 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 185N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)pyridin-4-yl)-[1,2,4]triazolo0.0044 0.0067 0.0468 [4,3-c]pyrimidin-5-amine 186(2R)-1-(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]0.0035 0.006 0.0068pyrimidin-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol 187(2S)-1-(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]0.0082 0.0125 0.012pyrimidin-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol 188N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-isopropyl-5-methyl-1H-pyrazol-4-yl)-0.0023 0.0038 0.0036 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1892-(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0042 0.0087 0.0052 5-methyl-1H-pyrazol-1-yl)ethanol 1902-(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0045 0.0171 0.0025 3-methyl-1H-pyrazol-1-yl)ethanol 1918-(4-(difluoromethyl)pyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0038 0.0131 0.0344 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1928-(1-cyclopropyl-1H-pyrazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.0035 0.0126 0.0104 triazolo[4,3-c]pyrimidin-5-amine 193N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(fluoromethyl)pyridin-3-yl)-[1,2,4]0.004 0.013 0.0054 triazolo[4,3-c]pyrimidin-5-amine 1948-(2,5-dimethylpyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0024 0.007 0.0241 [4,3-c]pyrimidin-5-amine 1958-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0059 0.0116 0.0024 [4,3-c]pyrimidin-5-amine 1968-(6-ethoxy-4-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0036 0.0082 0.0263 [4,3-c]pyrimidin-5-amine 1978-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0022 0.0057 0.0149 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1988-(2-(difluoromethyl)-5-methylpyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0044 0.0173 0.0078 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1995-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0042 0.0072 0.005 N,N,6-trimethylpicolinamide 2008-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0075 0.0095 0.003 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2018-(2-(difluoromethyl)-6-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0059 0.0073 0.0036 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 202N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridazin-4-yl)-[1,2,4]triazolo[4,3-c]0.0096 0.0187 0.0206 pyrimidin-5-amine 203N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-7-methyl-8-(2-methylpyridin-3-yl)-[1,2,4]0.0424 0.3385 N/A triazolo[4,3-c]pyrimidin-5-amine 2043-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0106 0.0193 0.0103 2-methylpyridine 1-oxide 205N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazin-2-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0073 0.0082 0.0167 amine 206N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0091 0.0095 0.0159 amine 207N-((5-fluorobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-0.0795 0.1817 0.0036 amine 208N-(benzofuran-4-ylmethyl)-8-(4-((dimethylamino)methyl)phenyl)-[1,2,4]triazolo0.0062 0.0127 0.0190 [4,3-c]pyrimidin-5-amine 209N-(benzofuran-4-ylmethyl)-8-(4-(4-methylpiperazin-1-yl)phenyl)-[1,2,4]triazolo0.0369 0.0290 0.1179 [4,3-c]pyrimidin-5-amine 210N-(benzofuran-4-ylmethyl)-8-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-[1,2,4]triazolo0.0185 0.0214 N/A [4,3-c]pyrimidin-5-amine 211N-(benzofuran-4-ylmethyl)-8-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo0.0322 0.0288 N/A [4,3-c]pyrimidin-5-amine 212N-(benzofuran-4-ylmethyl)-8-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-[1,2,4]triazolo0.0312 0.0338 N/A [4,3-c]pyrimidin-5-amine 213N-(benzofuran-4-ylmethyl)-8-(pyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0366 0.0256 N/A 214N-(benzofuran-4-ylmethyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[4,3-c]0.0374 0.0225 N/A pyrimidin-5-amine 215N-(benzofuran-4-ylmethyl)-8-(4-(isopropylsulfonyl)phenyl)-[1,2,4]triazolo[4,3-c]0.0203 0.0212 N/A pyrimidin-5-amine 216(4-(5-((benzofuran-4-ylmethyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.1315 0.1834 N/A phenyl)(pyrrolidin-1-yl)methanone 217N-(benzofuran-4-ylmethyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.3632 0.1113 N/A 218N-(benzofuran-4-ylmethyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0386 0.0263 N/A 2198-(4-((dimethylamino)methyl)phenyl)-N-((5-fluorobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0065 0.0068 0.0079 [4,3-c]pyrimidin-5-amine 220N-(benzofuran-4-ylmethyl)-8-(4-((1-methylpiperidin-4-yl)sulfonyl)phenyl)-[1,2,4]triazolo0.0141 0.0216 0.4667 [4,3-c]pyrimidin-5-amine 221N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-c]0.0091 0.0095 0.0159 pyrimidin-5-amine 2228-(4,6-dimethylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo0.0117 0.0140 0.0576 [4,3-c]pyrimidin-5-amine 2238-(6-((dimethylamino)methyl)-2-methylpyridin-3-yl)-N4(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0084 0.0184 0.0014 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2248-(6-ethyl-4-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.0015 0.0019 0.0022 triazolo[4,3-c]pyrimidin-5-amine 2258-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0075 0.0106 0.0045 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2268-(2-ethoxy-4-methylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0039 0.0050 0.0061 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 227(4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-0.0061 0.0075 0.0091 1-methyl-1H-pyrazol-5-yl)methanol 2288-(2-chloro-5-methylpyridin-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.0082 0.0090 0.0292 triazolo[4,3-c]pyrimidin-5-amine 2298-(6-ethyl-2-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]0.0059 0.0067 0.0027 triazolo[4,3-c]pyrimidin-5-amine 230N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methoxy-3-methylpyridin-4-yl)-[1,2,4]0.0129 0.0245 0.0252 triazolo[4,3-c]pyrimidin-5-amine 231N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyridin-2-yl)-[1,2,4]triazolo0.0061 0.0060 0.0358 [4,3-c]pyrimidin-5-amine 232N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-0.0062 0.0131 0.0133 c]pyrimidin-5-amine 233N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-imidazol-1-yl)-[1,2,4]triazolo0.0039 0.0115 0.0020 [4,3-c]pyrimidin-5-amine 234(5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)0.0054 0.0112 0.0045 pyridin-2-yl)methanol 2358-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine0.0399 0.0653 0.1918 2368-(2,4-dimethyl-1H-imidazol-1-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-0.0102 0.0232 0.0076 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 237N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-pyrazol-1-yl)-[1,2,4]triazolo0.0031 0.0100 0.0101 [4,3-c]pyrimidin-5-amine 238N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methyl-1H-1,2,4-triazol-1-yl)-0.0047 0.0144 0.0179 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 239N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4-methyl-1H-pyrazol-1-yl)-[1,2,4]triazolo0.0068 0.0159 0.0382 [4,3-c]pyrimidin-5-amine 240N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-imidazol-1-yl)-[1,2,4]0.0049 0.0143 0.0014 triazolo[4,3-c]pyrimidin-5-amine 241N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-1,2,4-triazol-1-yl)-[1,2,4]triazolo0.0113 0.0300 0.0284 [4,3-c]pyrimidin-5-amine 2425-fluoro-4-(((8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)0.0138 0.0500 0.0634 amino)methyl)-2,3-dihydrobenzofuran-3-ol 2435-fluoro-4-(((8-(2-(hydroxymethyl)pyridin-3-yl)-[1,2,4]triazolo[4,3-c]0.0154 0.0590 0.0409pyrimidin-5-yl)amino)methyl)-2,3-dihydrobenzofuran-3-ol 2443-(5-(((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo0.0117 0.0389 0.2415 [4,3-c]pyrimidin-8-yl)-2-methylpyridine 1-oxide 2458-(1,2-dimethyl-1H-imidazol-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)0.0672 0.2232 N/A methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

Table 4 below lists antiproliferative activities (IC₅₀ values) in B celllymphoma cell KARPAS422 after 14 days of treatment for the followingexamples

TABLE 4 Ex IC₅₀ # (μM) 1 0.0004 2 0.0030 3 0.0007 4 0.0003 5 0.0008 60.0002 7 0.0030 8 0.0006 9 0.0006 10 0.0174 207 0.0010

Accordingly, the compounds of the present disclosure have been found toinhibit EED and therefore useful in the treatment of diseases ordisorders associated with EED and PRC2, which include, but are notlimited to, diffused large B cell lymphoma (DLBCL), follicular lymphoma,other lymphomas, leukemia, multiple myeloma, mesothelioma, gastriccancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostatecancer, breast carcinoma, bile duct and gallbladder cancers, bladdercarcinoma, brain tumors including neurobalstoma, glioma, glioblastomaand astrocytoma, cervical cancer, colon cancer, melanoma, endometrialcancer, esophageal cancer, head and neck cancer, lung cancer,nasopharhyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cellcarcinoma, rectal cancer, thyroid cancers, parathyroid tumors, uterinetumors, and soft tissue sarcomas selected from rhabdomyosarcoma (RMS),Kaposi sarcoma, synovial sarcoma, osteosarcoma and Ewing's sarcoma.

V. PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS

The compounds of the present invention are typically used as apharmaceutical composition (e.g., a compound of the present inventionand at least one pharmaceutically acceptable carrier). A“pharmaceutically acceptable carrier (diluent or excipient)” refers tomedia generally accepted in the art for the delivery of biologicallyactive agents to animals, in particular, mammals, including, generallyrecognized as safe (GRAS) solvents, dispersion media, coatings,surfactants, antioxidants, preservatives (e.g., antibacterial agents,antifungal agents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, buffering agents (e.g., maleicacid, tartaric acid, lactic acid, citric acid, acetic acid, sodiumbicarbonate, sodium phosphate, and the like), disintegration agents,lubricants, sweetening agents, flavoring agents, dyes, and the like andcombinations thereof, as would be known to those skilled in the art(see, for example, Allen, L. V., Jr. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012). For purposes of this invention, solvates and hydrates areconsidered pharmaceutical compositions comprising a compound of thepresent invention and a solvent (i.e., solvate) or water (i.e.,hydrate).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above.

The compounds of this disclosure can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The compound of the present invention is typically formulated intopharmaceutical dosage forms to provide an easily controllable dosage ofthe drug and to give the patient an elegant and easily handleableproduct. The dosage regimen for the compounds of the present disclosurewill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. Compounds of this disclosure may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

In certain instances, it may be advantageous to administer the compoundof the present invention in combination with at least one additionalpharmaceutical (or therapeutic) agent, such as other anti-cancer agents,immunomodulators, anti-allergic agents, anti-nausea agents (oranti-emetics), pain relievers, cytoprotective agents, and combinationsthereof.

The term “combination therapy” refers to the administration of two ormore therapeutic agents to treat a therapeutic disease, disorder orcondition described in the present disclosure. Such administrationencompasses co-administration of these therapeutic agents in asubstantially simultaneous manner, such as in a single capsule having afixed ratio of active ingredients. Alternatively, such administrationencompasses co-administration in multiple, or in separate containers(e.g., capsules, powders, and liquids) for each active ingredient. Thecompound of the present disclosure and additional therapeutic agents canbe administered via the same administration route or via differentadministration routes. Powders and/or liquids may be reconstituted ordiluted to a desired dose prior to administration. In addition, suchadministration also encompasses use of each type of therapeutic agent ina sequential manner, either at approximately the same time or atdifferent times. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

General chemotherapeutic agents considered for use in combinationtherapies include anastrozole (Arimidex®), bicalutamide (Casodex®),bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection(Busulfex®), capecitabine (Xeloda®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®),carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®),cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®),cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomeinjection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXomeS), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (VepesidO), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phoenix(Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustineimplant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®),6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecanhydrochloride for injection (Hycamptin®), vinblastine (Velban®),vincristine (Oncovin®), and vinorelbine (Navelbine®).

Anti-cancer agents of particular interest for combinations with thecompounds of the present disclosure include:

Cyclin-Dependent Kinase (CDK) inhibitors: (Chen, S. et al., Nat CellBiol., 12(11):1108-14 (2010); Zeng, X. et al., Cell Cycle, 10(4):579-83(2011)) Aloisine A; Alvocidib (also known as flavopiridol or HMR-1275,2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone,and described in U.S. Pat. No. 5,621,002); Crizotinib (PF-02341066, CAS877399-52-5);2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one,hydrochloride (P276-00, CAS 920113-03-7);1-Methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine(RAF265, CAS 927880-90-8); Indisulam (E7070); Roscovitine (CYC202);6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one,hydrochloride (PD0332991); Dinaciclib (SCH727965);N-[5-[[(5-tert-Butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide(BMS 387032, CAS 345627-80-7);4-[[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoicacid (MLN8054, CAS 869363-13-3);5-[3-(4,6-Difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine(AG-024322, CAS 837364-57-5);4-(2,6-Dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acidN-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2);4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine(AZD5438, CAS 602306-29-6); Palbociclib (PD-0332991); and(2R,3R)-3-[[2-[[3-[[S(R)]—S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol(BAY 10000394).

Checkpoint Kinase (CHK) inhibitors: (Wu, Z. et al., Cell Death Differ.,18(11):1771-9 (2011)) 7-Hydroxystaurosporine (UCN-01);6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine(SCH900776, CAS 891494-63-6);5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acidN—[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8);4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7-AAD),Isogranulatimide, debromohymenialdisine;N-[5-Bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N′-(5-methyl-2-pyrazinyl)urea(LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7,4-Methylsulfinylbutyl isothiocyanate);9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A(YGRKKRRQRRRLYRSPAMPENL), and CBP501((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and(αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-Cyclohexaneacetamide(PF-0477736).

Protein Kinase B (PKB) or AKT inhibitors: (Rojanasakul, Y., Cell Cycle,12(2):202-3 (2013); Chen B. et al., Cell Cycle, 12(1):112-21 (2013))8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK-2206, CAS 1032349-93-1); Perifosine (KRX0401);4-Dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS1191951-57-1);4-[2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3S)-3-piperidinylmethoxy]-1H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol(GSK690693, CAS 937174-76-0);8-(1-Hydroxyethyl)-2-methoxy-3-[(4-methoxyphenyl)methoxy]-6H-dibenzo[b,d]pyran-6-one(palomid 529, P529, or SG-00529); Tricirbine(6-Amino-4-methyl-8-(β-D-ribofuranosyl)-4H,8H-pyrrolo[4,3,2-de]pyrimido[4,5-c]pyridazine);(αS)-α-[[[5-(3-Methyl-1H-indazol-5-yl)-3-pyridinyl]oxy]methyl]-benzeneethanamine(A674563, CAS 552325-73-2);4-[(4-Chlorophenyl)methyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine(CCT128930, CAS 885499-61-6); 4-(4-Chlorophenyl)-4-[4-(1Hpyrazol-4-yl)phenyl]-piperidine (AT7867, CAS 857531-00-1); and Archexin(RX-0201, CAS 663232-27-7).

C-RAF Inhibitors: (Chang, C. et al., Cancer Cell, 19(1):86-100 (2011))Sorafenib (Nexavar®);3-(Dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide(ZM336372, CAS 208260-29-1); and3-(1-cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide(AZ628, CAS 1007871-84-2).

Phosphoinositide 3-kinase (P13K) inhibitors: (Gonzalez, M. et al.,Cancer Res., 71(6): 2360-2370 (2011))4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine(also known as GDC 0941 and described in PCT Publication Nos. WO09/036082 and WO 09/055730);2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile(also known as BEZ235 or NVP-BEZ 235, and described in PCT PublicationNo. WO 06/122806);4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine(also known as BKM120 or NVP-BKM120, and described in PCT PublicationNo. WO2007/084786); Tozasertib (VX680 or MK-0457, CAS 639089-54-6);(5Z)-5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione(GSK1059615, CAS 958852-01-2);(1E,4S,4aR,5R,6aS,9aR)-5-(Acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-cyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8);8-Phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6);2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (SAR 245409 or XL 765);1,3-Dihydro-8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-(1-piperazinyl)-3-(trifluoromethyl)phenyl]-2H-imidazo[4,5-c]quinolin-2-one,(2Z)-2-butenedioate (1:1) (BGT 226);5-Fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)ethyl]-4(3H)-quinazolinone (CAL101);2-Amino-N-[3-[N-[3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide(SAR 245408 or XL 147); and (S)-Pyrrolidine-1,2-dicarboxylic acid2-amide1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide)(BYL719).

BCL-2 inhibitors: (Béguelin, W. et al., Cancer Cell, 23(5):677-92(2013))4-[4-[[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide(also known as ABT-263 and described in PCT Publication No. WO09/155386); Tetrocarcin A; Antimycin; Gossypol ((−)BL-193); Obatoclax;Ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4Hchromone-3-carboxylate(HA14-1); Oblimersen (G3139, Genasense®); Bak BH3 peptide; (−)-Gossypolacetic acid (AT-101);4-[4-[(4′-Chloro[1,1′-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide(ABT-737, CAS 852808-04-9); and Navitoclax (ABT-263, CAS 923564-51-6).

Mitogen-activated protein kinase (MEK) inhibitors: (Chang, C. J. et al.,Cancer Cell, 19(1):86-100 (2011)) XL-518 (also known as GDC-0973, CasNo. 1029872-29-4, available from ACC Corp.); Selumetinib(5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide,also known as AZD6244 or ARRY 142886, described in PCT Publication No.WO2003077914); Benimetinib(6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxyethyoxy)-amide, also known as MEK162, CAS 1073666-70-2,described in PCT Publication No. WO2003077914);2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide(also known as CI-1040 or PD184352 and described in PCT Publication No.WO2000035436);N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide(also known as PD0325901 and described in PCT Publication No.WO2002006213);2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also knownas U0126 and described in U.S. Pat. No. 2,779,780);N-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide(also known as RDEA119 or BAY869766 and described in PCT Publication No.WO2007014011);(3S,4R,5Z,8S,9S,11E)-14-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No.WO2003076424); 2′-Amino-3′-methoxyflavone (also known as PD98059available from Biaffin GmbH & Co., KG, Germany); Vemurafenib (PLX-4032,CAS 918504-65-1);(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS1204531-26-9); Trametinib dimethyl sulfoxide (GSK-1120212, CAS1204531-25-80);2-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide(AZD 8330); and3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide(CH 4987655 or Ro 4987655).

Aromatase inhibitors: (Pathiraja, T. et al., Sci. Transl. Med.,6(229):229 ra41 (2014)) Exemestane (Aromasin®); Letrozole (Femara®); andAnastrozole (Arimidex®).

Topoisomerase II inhibitors: (Bai, J. et al., Cell Prolif., 47(3):211-8(2014)) Etoposide (VP-16 and Etoposide phosphate, Toposar®, VePesid® andEtopophos®); Teniposide (VM-26, Vumon®); and Tafluposide.

SRC inhibitors: (Hebbard, L., Oncogene, 30(3):301-12 (2011)) Dasatinib(Sprycel®); Saracatinib (AZD0530, CAS 379231-04-6); Bosutinib (SKI-606,CAS 380843-75-4);5-[4-[2-(4-Morpholinyl)ethoxy]phenyl]-N-(phenylmethyl)-2-pyridineacetamide(KX2-391, CAS 897016-82-9); and4-(2-Chloro-5-methoxyanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(AZM475271, CAS 476159-98-5).

Histone deacetylase (HDAC) inhibitors: (Yamaguchi, J. et al., CancerSci., 101(2):355-62 (2010)) Voninostat (Zolinza®); Romidepsin(Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®,Suberoylanilide hydroxamic acid); Pyroxamide(syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A);Trapoxin B (RF-10238);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl](Cyl-2);Cyclic[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiraneoctanoyl-D-prolyl](HC-toxin);Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl](WF-3161); Chlamydocin((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiraneoctanoyl);Apicidin(Cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl);Romidepsin (Istodax®, FR-901228); 4-Phenylbutyrate; Spiruchostatin A;Mylproin (Valproic acid); Entinostat (MS-275,N-(2-Aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide);and Depudecin(4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-Undeca-1,6-dienitol).

Anti-tumor antibiotics: (Bai, J. et al., Cell Prolif., 47(3):211-8(2014)) Doxorubicin (Adriamycin® and Rubex®); Bleomycin (Lenoxane®);Daunorubicin (dauorubicin hydrochloride, daunomycin, and rubidomycinhydrochloride, Cerubidine®); Daunorubicin liposomal (daunorubicincitrate liposome, DaunoXome®); Mitoxantrone (DHAD, Novantrone®);Epirubicin (Ellence™); Idarubicin (Idamycin®, Idamycin PFS®); MitomycinC (Mutamycin®); Geldanamycin; Herbimycin; Ravidomycin; andDesacetylravidomycin.

Demethylating agents: (Musch, T. et al., PLoS One, (5): e10726 (2010))5-Azacitidine (Vidaza®); and Decitabine (Dacogen®).

Anti-estrogens: (Bhan, A. et al., J Mol Biol., S0022-2836 (14)₀₀₃₇₃-8(2014)) Tamoxifen (Novaldex®); Toremifene (Fareston®); and Fulvestrant(Faslodex®).

Some patients may experience allergic reactions to the compounds of thepresent invention and/or other anti-cancer agent(s) during or afteradministration; therefore, anti-allergic agents are often administeredto minimize the risk of an allergic reaction. Suitable anti-allergicagents include corticosteroids (Knutson, S., et al., PLoS One,DOI:10.1371/journal.pone.0111840 (2014)), such as dexamethasone (e.g.,Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (alsoknown as cortisone, hydrocortisone sodium succinate, hydrocortisonesodium phosphate, and sold under the tradenames Ala-Cort®,hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® andLanacort®), prednisolone (sold under the tradenames Delta-Cortel®,Orapred®, Pediapred® and Prelone®), prednisone (sold under thetradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®),methylprednisolone (also known as 6-methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate, soldunder the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® andSolu-Medrol®); antihistamines, such as diphenhydramine (e.g.,Benadryl®), hydroxyzine, and cyproheptadine; and bronchodilators, suchas the beta-adrenergic receptor agonists, albuterol (e.g., Proventil®),and terbutaline (Brethine®).

Immunomodulators of particular interest for combinations with thecompounds of the present disclosure include one or more of: an activatorof a costimulatory molecule or an inhibitor of an immune checkpointmolecule (e.g., one or more inhibitors of PD-1, PD-L1, LAG-3, TIM-3 orCTLA4) or any combination thereof.

In certain embodiments, the immunomodulator is an activator of acostimulatory molecule. In one embodiment, the agonist of thecostimulatory molecule is chosen from an agonist (e.g., an agonisticantibody or antigen-binding fragment thereof, or a soluble fusion) ofOX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB(CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7,NKp80, CD160, B7-H3 or CD83 ligand.

In certain embodiments, the immunomodulator is an inhibitor of an immunecheckpoint molecule. In one embodiment, the immunomodulator is aninhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT,LAIR1, CD160, 2B4 and/or TGFR beta. In one embodiment, the inhibitor ofan immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3 orCTLA4, or any combination thereof. The term “inhibition” or “inhibitor”includes a reduction in a certain parameter, e.g., an activity, of agiven molecule, e.g., an immune checkpoint inhibitor. For example,inhibition of an activity, e.g., a PD-1 or PD-L1 activity, of at least5%, 10%, 20%, 30%, 40% or more is included by this term. Thus,inhibition need not be 100%.

Some patients may experience nausea during and after administration ofthe compound of the present invention and/or other anti-cancer agent(s);therefore, anti-emetics are used in preventing nausea (upper stomach)and vomiting. Suitable anti-emetics include aprepitant (Emend®),ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®.dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant(Rezonic® and Zunrisa®), and combinations thereof.

Medication to alleviate the pain experienced during the treatment periodis often prescribed to make the patient more comfortable. Commonover-the-counter analgesics, such Tylenol®, are often used. However,opioid analgesic drugs such as hydrocodone/paracetamol orhydrocodone/acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph®or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphonehydrochloride (Opana®), and fentanyl (e.g., Duragesic®) are also usefulfor moderate or severe pain.

In an effort to protect normal cells from treatment toxicity and tolimit organ toxicities, cytoprotective agents (such as neuroprotectants,free-radical scavengers, cardioprotectors, anthracycline extravasationneutralizers, nutrients and the like) may be used as an adjunct therapy.Suitable cytoprotective agents include Amifostine (Ethyol®), glutamine,dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® orTotect®), xaliproden (Xaprila®), and leucovorin (also known as calciumleucovorin, citrovorum factor and folinic acid).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

In one embodiment, the present invention provides pharmaceuticalcompositions comprising at least one compound of the present invention(e.g., a compound of the present invention) or a pharmaceuticallyacceptable salt thereof together with a pharmaceutically acceptablecarrier suitable for administration to a human or animal subject, eitheralone or together with other anti-cancer agents.

In one embodiment, the present invention provides methods of treatinghuman or animal subjects suffering from a cellular proliferativedisease, such as cancer. The present invention provides methods oftreating a human or animal subject in need of such treatment, comprisingadministering to the subject a therapeutically effective amount of acompound of the present invention (e.g., a compound of the presentinvention) or a pharmaceutically acceptable salt thereof, either aloneor in combination with other anti-cancer agents.

In particular, compositions will either be formulated together as acombination therapeutic or administered separately.

In combination therapy for treatment of a malignancy, the compound ofthe present disclosure and other anti-cancer agent(s) may beadministered simultaneously, concurrently or sequentially with nospecific time limits, wherein such administration providestherapeutically effective levels of the two compounds in the body of thesubject.

In a preferred embodiment, the compound of the present disclosure andthe other anti-cancer agent(s) is generally administered sequentially inany order by infusion or orally. The dosing regimen may vary dependingupon the stage of the disease, physical fitness of the patient, safetyprofiles of the individual drugs, and tolerance of the individual drugs,as well as other criteria well-known to the attending physician andmedical practitioner(s) administering the combination. The compound ofthe present invention and other anti-cancer agent(s) may be administeredwithin minutes of each other, hours, days, or even weeks apart dependingupon the particular cycle being used for treatment. In addition, thecycle could include administration of one drug more often than the otherduring the treatment cycle and at different doses per administration ofthe drug.

In another aspect of the present invention, kits that include one ormore compound of the present invention and a combination partner asdisclosed herein are provided. Representative kits include (a) acompound of the present invention or a pharmaceutically acceptable saltthereof, (b) at least one combination partner, e.g., as indicated above,whereby such kit may comprise a package insert or other labelingincluding directions for administration.

A compound of the present invention may also be used to advantage incombination with known therapeutic processes, for example, theadministration of hormones or especially radiation. A compound of thepresent invention may in particular be used as a radiosensitizer,especially for the treatment of tumors which exhibit poor sensitivity toradiotherapy.

In another aspect of the present invention, kits that include one ormore compound of the present disclosure and a combination partner asdisclosed herein are provided. Representative kits include (a) acompound of the present disclosure or a pharmaceutically acceptable saltthereof, (b) at least one combination partner, e.g., as indicated above,whereby such kit may comprise a package insert or other labelingincluding directions for administration.

In the combination therapies of the invention, the compound of thepresent disclosure and the other therapeutic agent may be manufacturedand/or formulated by the same or different manufacturers. Moreover, thecompound of the present invention and the other therapeutic (orpharmaceutical agent) may be brought together into a combinationtherapy: (i) prior to release of the combination product to physicians(e.g. in the case of a kit comprising the compound of the invention andthe other therapeutic agent); (ii) by the physician themselves (or underthe guidance of the physician) shortly before administration; (iii) inthe patient themselves, e.g. during sequential administration of thecompound of the invention and the other therapeutic agent.

The compounds of the present disclosure are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving EED and/or PRC2. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving myeloperoxidase activity. For example, a compound ofthe present disclosure could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present disclosure couldbe used to test their effectiveness. The compounds of the presentdisclosure may also be used in diagnostic assays involving EED and/orPRC2.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

1-19. (canceled)
 20. A method of making a compound of Formula (I), or apharmaceutically acceptable salt thereof:

wherein:

is a single bond or a double bond; R¹ and R² are independently H orhalogen; R³ is independently selected from: halogen, phenyl, and a 5- to6-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(a), O, and S(O)_(p); wherein said phenyl andheteroaryl are substituted with 0-3 R^(3A); each R^(3A) is independentlyselected from: halogen, CN, —(O)_(m)—(C₁-C₆ alkyl substituted with 0-1R^(3B)), C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, R^(3C), —OR^(3C),—C(═O)R^(3D), NR^(3E)R^(3F), —C(═O)NR^(3E)R^(3F), —NHC(═O)R^(3D),—S(═O)₂R^(3D), —S(═O)₂NR^(3E)R^(3F), NHS(═O)₂(C₁-C₄ alkyl), and—CR^(3C)R^(3E)R^(3G); R^(3B) is independently selected from: OH,NR^(e)R^(f), C₁-C₄ alkoxy, —C(═O)NR^(e)R^(f), —S(═O)₂(C₁-C₄ alkyl),—NHC(═O)(C₁-C₄ alkyl), and a 5- to 6-membered heterocycloalkylcomprising carbon atoms and 1-2 heteroatoms selected from N, NR^(a), O,and S(O)_(p); wherein said heterocycloalkyl is substituted with 0-2R^(c); each R^(3C) is independently selected from: C₃-C₆ cycloalkyl,phenyl, and a 4- to 7-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR^(a), O, and S(O)_(p); wherein eachmoiety is substituted with 0-2 R^(c); each R^(3D) is independentlyselected from: C₁-C₄ alkyl and R^(3C); R^(3E) and R^(3G) are, at eachoccurrence, independently selected from: H and C₁-C₄ alkyl; each R^(3F)is independently selected from: H and C₁-C₄ alkyl substituted with 0-1R^(d); R⁴ is independently selected from: H, halogen and C₁-C₄ alkyl; R⁵is independently selected from OH and C₁-C₄ alkyl; each R^(a) isindependently selected from: H, →O, C₁-C₄ alkyl substituted with 0-1R^(b), —C(═O)H, —C(═O)(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), C₃-C₆cycloalkyl, and benzyl; R^(b) is independently selected from: halogen,OH and C₁-C₄ alkoxy; each R^(c) is independently selected from: ═O,halogen, OH, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy; R^(d) is independently selected from: OH and NR^(e)R^(f);R^(e) and R^(f) are, at each occurrence, independently selected from: Hand C₁-C₄ alkyl; each p is independently selected from 0, 1 and 2; and mand n are, at each occurrence, independently selected from 0 and 1;wherein the method comprises the following steps: i) treating pyrimidine(1) with hydrazine to produce a 4-hydrazinyl pyrimidine (2)

where X is Br or F; ii) converting 4-hydrazinyl pyrimidine (2) withtrimethyl orthoformate to triazole product (3)

where X is Br or F; iii) conducting a substitution reaction of triazoleproduct (3) with a compound (A) to produce compound (4)

where X is Br or F; iv) conducting a coupling reaction of compound (4)with reagent R³—B, in the presence of a palladium catalyst, to producethe compound of Formula (I)

where: X is Br or F; R³ is as defined above, and B is


21. The method of claim 20, wherein compound (A) is selected from thegroup consisting of:


22. The method of claim 20, wherein compound (A) is selected from thegroup consisting of:


23. The method of claim 20, wherein compound (4) is selected from thegroup consisting of:


24. The method of claim 20, wherein compound (4) is


25. The method of claim 20, wherein R³—B is selected from the groupconsisting of:


26. The method of claim 20, wherein R³—B is selected from the groupconsisting of:


27. The method of claim 20, wherein: compound (A) is

R³—B

and the compound of Formula (I) is


28. A compound, or a pharmaceutically acceptable salt thereof, havingthe formula:

wherein: R¹ is H or halogen; R² is H or halogen; each R⁵ isindependently selected from OH and C₁-C₄ alkyl; and n is selected from 0and
 1. 29. The compound of claim 28, wherein the compound is selectedfrom the group consisting of:


30. The compound of claim 28, wherein the compound is


31. The compound of claim 28, wherein the compound is


32. A compound, or a pharmaceutically acceptable salt thereof, havingthe formula:

wherein: R¹ is H or halogen; R² is H or halogen; each R⁵ isindependently selected from OH and C₁-C₄ alkyl; P is an amine protectinggroup, and n is selected from 0 and
 1. 33. The compound of claim 32,wherein the compound is


34. A compound, or a pharmaceutically acceptable salt thereof, havingthe formula:

wherein: R¹ is halogen; R² is H or halogen; each R⁵ is independentlyselected from OH and C₁-C₄ alkyl; and n is selected from 0 and
 1. 35.The compound of claim 34, wherein the compound is


36. A compound of Formula (4), or a pharmaceutically acceptable saltthereof:

wherein: X is Br or F; R¹ is H or halogen; R² is H or halogen; each R⁵is independently selected from OH and C₁-C₄ alkyl; and n is selectedfrom 0 and
 1. 37. The compound of claim 36, wherein the compound ofFormula (4) has the following formula, or a pharmaceutically acceptablesalt thereof:


38. The compound of claim 37, wherein the compound of Formula (4) is

or a pharmaceutically acceptable salt thereof.
 39. A compound of Formula(4′), or a pharmaceutically acceptable salt thereof:

wherein: X is Br or F; P is an amine protecting group; R¹ is H orhalogen; R² is H or halogen; each R⁵ is independently selected from OHand C₁-C₄ alkyl; and n is selected from 0 and
 1. 40. The compound ofclaim 39, wherein the compound of Formula (4′) has the followingformula, or a pharmaceutically acceptable salt thereof:


41. The compound of claim 40, wherein the compound of Formula (4) is

or a pharmaceutically acceptable salt thereof.